Article

Vitamin D Deficiency and the Risk of Cerebrovascular Disease

Abstract and Figures

Vitamin D deficiency has been clearly linked to major chronic diseases associated with oxidative stress, inflammation, and aging, including cardiovascular and neurodegenerative diseases, diabetes, and cancer. In particular, the cardiovascular system appears to be highly sensitive to vitamin D deficiency, as this may result in endothelial dysfunction and vascular defects via multiple mechanisms. Accordingly, recent research developments have led to the proposal that pharmacological interventions targeting either vitamin D deficiency or its key downstream effects, including defective autophagy and abnormal pro-oxidant and pro-inflammatory responses, may be able to limit the onset and severity of major cerebrovascular diseases, such as stroke and cerebrovascular malformations. Here we review the available evidence supporting the role of vitamin D in preventing or limiting the development of these cerebrovascular diseases, which are leading causes of disability and death all over the world.
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antioxidants
Review
Vitamin D Deficiency and the Risk of
Cerebrovascular Disease
Hyun Ah Kim 1, 2, , Andrea Perrelli 3, 4, , Alberto Ragni 5, , Francesca Retta 5, ,
T. Michael De Silva 1,2, Christopher G. Sobey 1, 2, * and Saverio Francesco Retta 3, 4, *
1Department of Physiology, Anatomy & Microbiology and Centre for Cardiovascular and Biology Disease
Research, School of Life Sciences, La Trobe University, Bundoora 3086, Australia;
H.Kim2@latrobe.edu.au (H.A.K.); T.DeSilva@latrobe.edu.au (T.M.D.S.)
2Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology,
Monash University, Clayton 3800, Australia
3Department of Clinical and Biological Sciences, University of Torino, Orbassano, 10043 Torino, Italy;
andrea.perrelli@unito.it
4CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological
Sciences, University of Torino, Orbassano, 10043 Torino, Italy
5
Oncological Endocrinology Unit, Department of Medical Sciences, Citt
à
della Salute e della Scienza Hospital,
University of Torino, 10126 Torino, Italy; alberto.ragni@edu.unito.it (A.R.); francesca.retta@edu.unito.it (F.R.)
*Correspondence: c.sobey@latrobe.edu.au (C.G.S.); francesco.retta@unito.it (S.F.R.);
Tel.: +61-3-94791316 (C.G.S.); +39-011-6706426 (S.F.R.)
These authors share first authorship.
Received: 28 February 2020; Accepted: 15 April 2020; Published: 17 April 2020


Abstract:
Vitamin D deficiency has been clearly linked to major chronic diseases associated with
oxidative stress, inflammation, and aging, including cardiovascular and neurodegenerative diseases,
diabetes, and cancer. In particular, the cardiovascular system appears to be highly sensitive to
vitamin D deficiency, as this may result in endothelial dysfunction and vascular defects via multiple
mechanisms. Accordingly, recent research developments have led to the proposal that pharmacological
interventions targeting either vitamin D deficiency or its key downstream eects, including defective
autophagy and abnormal pro-oxidant and pro-inflammatory responses, may be able to limit the onset
and severity of major cerebrovascular diseases, such as stroke and cerebrovascular malformations.
Here we review the available evidence supporting the role of vitamin D in preventing or limiting the
development of these cerebrovascular diseases, which are leading causes of disability and death all
over the world.
Keywords:
cerebrovascular disease; stroke; cerebral cavernous malformation (CCM); vitamin D;
oxidative stress; inflammation; endothelial dysfunction; redox homeostasis and signaling; autophagy;
antioxidant and anti-inflammatory defenses
1. Sources, Metabolism, and Pleiotropic Functions of Vitamin D
The term vitamin D refers to a group of lipid-soluble secosteroid compounds with pro-hormone
activities, of which five forms have been described: vitamin D
1
, D
2
, D
3
, D
4
, and D
5
. Among these, the
most important for human biology are vitamin D
2
(also known as ergocalciferol), which is produced in
plants and fungi from the precursor ergosterol upon exposure to the sun’s ultraviolet B (UVB) rays, and
vitamin D
3
(also known as cholecalciferol), which is mainly produced in the skin from the precursor
7-dehydrocholesterol (7-DHC) upon exposure to UVB rays and may also be obtained from animal
sources or dietary supplements. Both vitamins D
2
and D
3
are transported in the blood by carrier proteins,
mainly by vitamin D binding protein (VDBP), but also by albumin and lipoproteins, and distributed
Antioxidants 2020,9, 327; doi:10.3390/antiox9040327 www.mdpi.com/journal/antioxidants
Antioxidants 2020,9, 327 2 of 22
to other tissues (primarily the liver). In the liver, they are hydroxylated at C-25 by 25-hydroxylase
enzymes of the cytochrome P450 monooxygenase (CYP) family (mostly but not exclusively CYP2R1
and CYP27A1) to generate the main circulating form of vitamin D: 25-hydroxy-vitamin D (25(OH)D).
The 25(OH)D is then transported by vitamin D binding proteins via the blood to the kidneys, where it is
internalized by renal proximal tubular cells through receptor (megalin)-mediated endocytosis. There it
undergoes a further hydroxylation at C-1 by the mitochondrial 1-alpha-hydroxylase enzyme (CYP27B1),
to produce the hormonally active form of vitamin D, 1,25-dihydroxy-vitamin D (1,25(OH)
2
D), which is
responsible for most, if not all of its biological actions [
1
4
]. Two forms of 1,25(OH)
2
D exist: 1,25(OH)
2
D
3
(calcitriol) and 1,25(OH)
2
D
2
(ercalcitriol), which are derived from cholecalciferol and ergocalciferol,
respectively. Although the kidneys are the major source of circulating 1,25(OH)
2
D, a number of other
tissues also express the CYP27B1 enzyme, which uniquely possesses 25(OH)D 1-alpha-hydroxylase
activity. Inactivation and catabolism of both 25(OH)D and 1,25(OH)
2
D are specifically mediated by the
24-hydroxylase activity of the mitochondrial CYP24A1 enzyme [2].
It is known that 1,25(OH)
2
D exerts its biological eects by binding to and activating the vitamin
D receptor (VDR), a member of the ligand-regulated nuclear receptor superfamily of transcription
factors widely distributed in the body, expressed by leukocytes [
5
], endothelial cells [
6
], astrocytes, and
neurons [
7
]. Both forms of 1,25(OH)
2
D can activate the VDR, with similar anity [
2
]. Upon activation
by ligand binding, VDR heterodimerizes with the retinoid X receptor (RXR) to form a transcriptionally
active complex [
1
,
8
,
9
]. Formation of the VDR/RXR-heterodimer and its binding to DNA is essential for
the regulation of gene transcription by 1,25(OH)
2
D [
9
]. In particular, the VDR/RXR complex binds
vitamin D response elements (VDREs), which are specific promoter sequences. Co-regulator factors
are then recruited to either increase or suppress the transcription of various target genes, including
genes involved in cell proliferation, dierentiation, apoptosis, inflammation, and oxidative stress [
10
]
(Figure 1).
Antioxidants 2020, 9, x FOR PEER REVIEW 2 of 21
and distributed to other tissues (primarily the liver). In the liver, they are hydroxylated at C-25 by 25-
hydroxylase enzymes of the cytochrome P450 monooxygenase (CYP) family (mostly but not
exclusively CYP2R1 and CYP27A1) to generate the main circulating form of vitamin D: 25-hydroxy-
vitamin D (25(OH)D). The 25(OH)D is then transported by vitamin D binding proteins via the blood
to the kidneys, where it is internalized by renal proximal tubular cells through receptor (megalin)-
mediated endocytosis. There it undergoes a further hydroxylation at C-1 by the mitochondrial 1-
alpha-hydroxylase enzyme (CYP27B1), to produce the hormonally active form of vitamin D, 1,25-
dihydroxy-vitamin D (1,25(OH)2D), which is responsible for most, if not all of its biological actions
[1–4]. Two forms of 1,25(OH)2D exist: 1,25(OH)2D3 (calcitriol) and 1,25(OH)2D2 (ercalcitriol), which
are derived from cholecalciferol and ergocalciferol, respectively. Although the kidneys are the major
source of circulating 1,25(OH)2D, a number of other tissues also express the CYP27B1 enzyme, which
uniquely possesses 25(OH)D 1-alpha-hydroxylase activity. Inactivation and catabolism of both
25(OH)D and 1,25(OH)2D are specifically mediated by the 24-hydroxylase activity of the
mitochondrial CYP24A1 enzyme [2].
It is known that 1,25(OH)2D exerts its biological effects by binding to and activating the vitamin
D receptor (VDR), a member of the ligand-regulated nuclear receptor superfamily of transcription
factors widely distributed in the body, expressed by leukocytes [5], endothelial cells [6], astrocytes,
and neurons [7]. Both forms of 1,25(OH)2D can activate the VDR, with similar affinity [2]. Upon
activation by ligand binding, VDR heterodimerizes with the retinoid X receptor (RXR) to form a
transcriptionally active complex [1,8,9]. Formation of the VDR/RXR-heterodimer and its binding to
DNA is essential for the regulation of gene transcription by 1,25(OH)2D [9]. In particular, the
VDR/RXR complex binds vitamin D response elements (VDREs), which are specific promoter
sequences. Co-regulator factors are then recruited to either increase or suppress the transcription of
various target genes, including genes involved in cell proliferation, differentiation, apoptosis,
inflammation, and oxidative stress [10] (Figure 1).
Figure 1. Vitamin D signaling pathway: 1,25-hydroxyvitamin D (1,25(OH)2D3), also known as
calcitriol, binds to the vitamin D receptor (VDR) and promotes its heterodimerization with the
retinoid X receptor (RXR). The activated VDR/RXR heterodimer then recruits coregulator complexes
and binds to the vitamin D response elements (VDRE) in the promoters of a large number of genes
Figure 1.
Vitamin D signaling pathway: 1,25-hydroxyvitamin D (1,25(OH)
2
D
3
), also known as calcitriol,
binds to the vitamin D receptor (VDR) and promotes its heterodimerization with the retinoid X
receptor (RXR). The activated VDR/RXR heterodimer then recruits coregulator complexes and binds
to the vitamin D response elements (VDRE) in the promoters of a large number of genes involved in
fundamental processes, including cell survival and immune response to injury, thus modulating their
transcription and subsequent eects in a ligand-dependent manner.
Antioxidants 2020,9, 327 3 of 22
VDR is expressed in more than 30 target tissues in humans [
11
], and a genome-wide analysis
revealed more than 1000 VDR-specific genomic binding sites in most tissues, suggesting that the
transcriptionally active form of vitamin D influences the expression of many genes likely to be relevant
for human health and disease [
12
]. Furthermore, lessons from VDR and CYP27B1 null mice indicate
that VDR may act either dependently or independently of 1,25(OH)
2
D. Thus, multiple receptors and
ligands may participate in the vitamin D endocrine system [
1
,
3
,
13
], in addition to non-genomic actions
via unclear mechanisms [
14
16
]. Indeed, consistent with the multiple biological functions of the
active form of vitamin D, there is evidence that VDR, which is normally localized in the nucleus and
associated with gene transcription, may also be present in the plasma membrane and mediate rapid
responses to 1,25(OH)2D [11,17].
Vitamin D plays a pivotal role in bone metabolism via calcium and phosphate homeostasis, whereby
it stimulates calcium absorption and reabsorption in the intestine and the kidneys, respectively; it also
contributes to the formation and resorption of bone tissue by promoting the dierentiation of osteoblasts
and regulating the eects by other bone-active molecules [16,18].
The ubiquitous expression of the VDR and the CYP27B1 enzyme has led to speculation that vitamin
D may exert physiological roles other than via calcium-phosphate homeostasis (i.e., non-classical
roles) [
14
,
19
]. Indeed, the physiological importance of vitamin D extends far beyond the regulation
of calcium homeostasis and bone metabolism. Vitamin D can regulate secretion of some hormones,
including parathyroid hormone (PTH), insulin, and fibroblast growth factor 23 (FGF23), and the eects
on PTH secretion are facilitated by using vitamin D analogues in the clinical treatment of secondary
hyperparathyroidism [
20
]. Vitamin D also plays an important role in regulating both innate and
adaptive immunity. For example, activated monocytes express CYP27B1 to produce 1,25(OH)
2
D and
induce antimicrobial peptides, and vitamin D suppresses the proliferation of both B and T lymphocytes,
particularly the T helper-1 and-17 cells that are capable of activating macrophages [
14
]. On the other
hand, regulatory T lymphocytes are increased by 1,25(OH)
2
D [
21
]. Consistent with the suppressive
eect of vitamin D on the adaptive immune system, vitamin D deficiency and VDR polymorphisms
are associated with increased risk of both systemic and organ-specific autoimmune diseases [
22
].
Moreover, an intervention trial has demonstrated that vitamin D could reduce the incidence of type 1
diabetes mellitus in Finnish infants (a population at high risk of developing autoimmune diseases) [
23
].
Vitamin D has also been shown to exert anti-proliferative and pro-dierentiating eects on many cell
types [24], leading to the evaluation of its potential anticancer activities in human trials [14,25].
The relationship between vitamin D and cardiovascular health has been extensively investigated.
The cardiovascular system appears to be a target for vitamin D, with VDR and 1-alpha hydroxylase
expressed in endothelial and vascular smooth muscle cells and cardiomyocytes, as well as in
macrophages and T-cells, which is also highly relevant to VDR action in the cardiovascular system [
26
].
Vitamin D regulates the contractility of vascular smooth muscle cells via modulation of calcium
influx, and appears to regulate endothelial function through its antioxidant eects and modulation
of cell survival and autophagy [
27
,
28
]. Calcitriol has also been reported to be a negative regulator
of the renin–angiotensin–aldosterone system [
29
], and thus vitamin D deficiency could contribute to
endothelial dysfunction and the onset of cardiovascular diseases (CVDs). Various studies have indeed
found an association between low circulating levels of 25(OH)D and the onset of hypertension, diabetes
mellitus, and other CVDs [
10
,
30
33
]. Vitamin D could perhaps prevent endothelial dysfunction and
atherosclerosis through its antioxidant and anti-inflammatory actions (e.g., inhibition of superoxide
anion generation, modulation of cytokine secretion, and inhibition of monocyte adhesion and
migration) [
27
,
34
37
]. More generally, as vitamin D deficiency is associated with many pathologies
resembling those induced by defective autophagy, it has been suggested that autophagy plays a
major role in the multiple health-promoting eects of vitamin D [
28
,
38
,
39
]. Autophagy is an essential
process for cell homeostasis [
40
], and plays a key role in cellular responses to oxidative stress and
inflammation [4144].
Antioxidants 2020,9, 327 4 of 22
2. Anti-Inflammatory Properties of Vitamin D
Serum vitamin D levels are inversely associated with interleukin (IL)-6 and high-sensitivity
C-reactive protein (hsCRP) levels in stroke individuals, consistent with a potential anti-inflammatory
role of vitamin D after stroke [
45
,
46
]. Experimental evidence has shown that activation of VDR
by calcitriol has immunomodulatory actions [
47
50
] and prevents leukocyte recruitment to injured
tissues [49,51,52].
Calcitriol exerts its immunomodulatory actions through a variety of mechanisms. It down-regulates
nuclear factor kappa-light-chain-enhancer of activated B cells (NF-
κ
B), a transcription factor involved
in inflammatory gene expression in lymphocytes [
53
], and can inhibit its activation by reducing DNA
binding of NF-
κ
B [
54
]. Vitamin D can also dampen inflammation after myocardial injury by inhibiting
the RhoA/Rho-associated protein kinase (ROCK)/NF-
κ
B pathway [
55
]. Furthermore, the VDR/RXR
complex binds to the nuclear factor of activated T cells (NFAT) binding site of the IL-2 promoter
and inhibits NFAT activity in T cells, thus blocking T cell proliferation [
56
] and leading to reduced
expression of IL-17A [
48
]. Calcitriol can modulate the phenotype of T cells by downregulating Janus
kinase (JAK)–signal transducer and activator of transcription (STAT) signaling, which is critical for the
development of pathogenic T helper (Th) cells, such as Th1 and Th17 cells [
57
59
], gamma-delta (
γδ
)
T cells [
60
], and their cytokine production [
61
]. Moreover, calcitriol can promote the polarization of
anti-inflammatory Th2 [
62
] and T regulatory (Treg) cells [
63
], thus inhibiting inflammation-driven injury.
Lastly, calcitriol can promote the generation of tolerogenic dendritic cells [
64
,
65
] and prevent the
release of pro-inflammatory cytokines from monocytes/macrophages via inhibition of the p38 MAP
kinase [
49
,
66
]. Likewise, it can inhibit atherosclerosis by promoting polarization of macrophages to an
M2-phenotype [
67
]. Calcitriol can similarly exert an anti-inflammatory action on human microglia
by facilitating M2 dierentiation and upregulation of the anti-inflammatory toll-like receptor (TLR)
10 [
68
]. Furthermore, calcitriol reduces the expression of pro-inflammatory cytokines via promoting
induction of the suppressor of cytokine signaling-3 (SOCS3) by IL-10 [69] (Figure 2A).
Antioxidants 2020, 9, x FOR PEER REVIEW 4 of 21
2. Anti-Inflammatory Properties of Vitamin D
Serum vitamin D levels are inversely associated with interleukin (IL)-6 and high-sensitivity C-
reactive protein (hsCRP) levels in stroke individuals, consistent with a potential anti-inflammatory
role of vitamin D after stroke [45,46]. Experimental evidence has shown that activation of VDR by
calcitriol has immunomodulatory actions [47–50] and prevents leukocyte recruitment to injured
tissues [49,51,52].
Calcitriol exerts its immunomodulatory actions through a variety of mechanisms. It down-
regulates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a transcription
factor involved in inflammatory gene expression in lymphocytes [53], and can inhibit its activation
by reducing DNA binding of NF-κB [54]. Vitamin D can also dampen inflammation after myocardial
injury by inhibiting the RhoA/Rho-associated protein kinase (ROCK)/NF-κB pathway [55].
Furthermore, the VDR/RXR complex binds to the nuclear factor of activated T cells (NFAT) binding
site of the IL-2 promoter and inhibits NFAT activity in T cells, thus blocking T cell proliferation [56]
and leading to reduced expression of IL-17A [48]. Calcitriol can modulate the phenotype of T cells by
downregulating Janus kinase (JAK)–signal transducer and activator of transcription (STAT)
signaling, which is critical for the development of pathogenic T helper (Th) cells, such as Th1 and
Th17 cells [57–59], gamma-delta (γδ) T cells [60], and their cytokine production [61]. Moreover,
calcitriol can promote the polarization of anti-inflammatory Th2 [62] and T regulatory (Treg) cells
[63], thus inhibiting inflammation-driven injury.
Lastly, calcitriol can promote the generation of tolerogenic dendritic cells [64,65] and prevent the
release of pro-inflammatory cytokines from monocytes/macrophages via inhibition of the p38 MAP
kinase [49,66]. Likewise, it can inhibit atherosclerosis by promoting polarization of macrophages to
an M2-phenotype [67]. Calcitriol can similarly exert an anti-inflammatory action on human microglia
by facilitating M2 differentiation and upregulation of the anti-inflammatory toll-like receptor (TLR)
10 [68]. Furthermore, calcitriol reduces the expression of pro-inflammatory cytokines via promoting
induction of the suppressor of cytokine signaling-3 (SOCS3) by IL-10 [69] (Figure 2A).
Figure 2. Vitamin D pleiotropic effects on anti-inflammatory (A) and antioxidant (B) signaling
pathways and mechanisms (see text for details). FoxO (Forkhead box-O); FoxP (Forkhead box-P);;
JAK (Janus kinase); IL (interleukin); INFγ (interferon-gamma); MAPK (mitogen-activated protein
kinase); mTOR (mammalian target of rapamycin); NFAT (nuclear factor of activated T cells); NF-κB
(nuclear factor kappa-light-chain-enhancer of activated B cells); NOX (NADPH oxidase); Nrf2
(nuclear factor erythroid 2-related factor 2); RhoA (RhoA GTPase); ROCK (Rho-associated protein
kinase); ROS (reactive oxygen species); SIRT1 (Sirtuin 1); SOCS3 (suppressor of cytokine signaling-3);
SOD (superoxide dismutase); STAT (signal transducer and activator of transcription); TLR (toll-like
receptor); TNFα (tumor necrosis factor alpha); γδ T (gamma-delta T cells); M1 (M1 macrophages); Th
(T helper cells); tolDCs (tolerogenic dendritic cells); Treg (regulatory T cells).
Figure 2.
Vitamin D pleiotropic eects on anti-inflammatory (
A
) and antioxidant (
B
) signaling pathways
and mechanisms (see text for details). FoxO (Forkhead box-O); FoxP (Forkhead box-P);; JAK (Janus
kinase); IL (interleukin); INF
γ
(interferon-gamma); MAPK (mitogen-activated protein kinase); mTOR
(mammalian target of rapamycin); NFAT (nuclear factor of activated T cells); NF-
κ
B (nuclear factor
kappa-light-chain-enhancer of activated B cells); NOX (NADPH oxidase); Nrf2 (nuclear factor erythroid
2-related factor 2); RhoA (RhoA GTPase); ROCK (Rho-associated protein kinase); ROS (reactive oxygen
species); SIRT1 (Sirtuin 1); SOCS3 (suppressor of cytokine signaling-3); SOD (superoxide dismutase);
STAT (signal transducer and activator of transcription); TLR (toll-like receptor); TNF
α
(tumor necrosis
factor alpha);
γδ
T (gamma-delta T cells); M1 (M1 macrophages); Th (T helper cells); tolDCs (tolerogenic
dendritic cells); Treg (regulatory T cells).
Antioxidants 2020,9, 327 5 of 22
Inflammation is well established to be a key contributing factor in secondary brain injury after
ischemic stroke, making this process a rational target for new therapies [
70
]. We recently explored
the eect of experimentally elevating levels of vitamin D in vitamin D-replete mice [
50
], analogous to
high-dose supplementation regimes in humans [
71
,
72
]. Acute supplementation of vitamin D reduced
infarct volume by ~50%, reduced the gene expression of pro-inflammatory mediators, and increased
the expression of the T regulatory cell marker, Forkhead box-P3 (FoxP3) [
50
]. Our findings not only
demonstrated a direct impact of vitamin D on the degree of inflammation and secondary brain injury
that developed following stroke, but indicated that acute calcitriol supplementation can actually limit
the resulting injury, even in vitamin D-sucient individuals [50].
3. Antioxidant Properties of Vitamin D
Among its potential pleiotropic roles in human health, it has been suggested that the active
form of vitamin D may act as a membrane antioxidant, protecting cell membranes against free
radical-induced lipid peroxidation through interaction with phospholipid fatty acid side chains,
in order to increase stabilization of the membrane structure [
73
]. Indeed, there is evidence that
vitamin D can be as eective as vitamin E, a major dietary lipid-soluble antioxidant, in reducing lipid
peroxidation and inducing the activity of reactive oxygen species (ROS) scavenging enzymes, such as
superoxide dismutase (SOD) [
74
]. Moreover, it has been reported that vitamin D can stimulate sirtuin
1 (SIRT1), a protein deacetylase known to exert cardioprotective eects, by increasing autophagy
and mitochondrial function via inhibition of the mTOR pathway and reducing oxidative stress and
inflammatory responses, via activation of FoxO-dependent antioxidant pathways and inhibition
of NF-
κ
B signaling, respectively [
75
78
]. Furthermore, vitamin D has been shown to exert an
antioxidant role by VDR-mediated transcriptional downregulation of NOX2, a major isoform of
NADPH oxidase [
79
], and upregulation of Nrf2, a master inducer of antioxidant responses [
80
82
]
(Figure 2B). Such an action is consistent with the upregulation of critical biomarkers of oxidative stress,
including 8-hydroxy-2’-deoxyguanosine (8-OHdG) observed in VDR knockout mice [83].
More generally, it appears that vitamin D acts as a guardian of cellular homeostasis and protects
from oxidative stress in various cell types, including human endothelial cells, through its ability to
regulate crosstalk between redox signaling and autophagy [
27
,
28
,
38
,
84
]. Accordingly, whereas it is
now well-established that autophagy serves as an essential cellular antioxidant system by removing
damaged or dysfunctional proteins and organelles [
40
,
41
,
85
], endothelial cell viability can be enhanced
by pre-treatment with vitamin D before the induction of oxidative stress [
27
]. Furthermore, despite some
controversy over the clinical relevance of the antioxidant properties of vitamin D [
86
], recent studies
have shown that vitamin D supplementation increases basal levels of autophagy and decreases oxidative
stress parameters, suggesting a therapeutic potential in oxidative stress-related diseases [
39
,
85
,
87
92
].
Indeed, vitamin D is known to exert antioxidant properties in the endothelium [
27
,
93
,
94
], and vitamin
D supplementation is reported to decrease the burden of pathological vascular phenotypes related to
oxidative stress in a mouse model of a cerebrovascular disease [95].
Nevertheless, an individual’s response to a given dose of vitamin D may be influenced by multiple
factors, including genetic modifiers, as analysis of primary tissues from vitamin D intervention studies
have indicated large interindividual variation for the ecacy of vitamin D supplementation, an issue
that should be carefully considered in clinical management [12,9698].
4. Determinants of Vitamin D Status and Related Health Outcomes
Serum concentration of 25(OH)D, the main circulating metabolite of vitamin D, is the best indicator
of vitamin D status, as it has a quite long half-life of 15 days and reflects both cutaneous synthesis
and dietary intake from foods and supplements. In contrast, circulating 1,25(OH)
2
D is generally
not considered a good biomarker of vitamin D status, mainly because it has a short half-life of
15 h, and its levels do not reflect strictly cutaneous synthesis and dietary intake. Although there is
currently no worldwide consensus on the optimal vitamin D status, serum 25(OH)D levels
75 nmol/L
Antioxidants 2020,9, 327 6 of 22
(30 ng/mL)
are generally considered adequate for overall health, whereas levels between 50 and
75 nmol/L
(20–30 ng/mL)
indicate “insuciency”, and levels <50 nmol/L (<20 ng/mL) indicate
“deficiency”. On the other hand, there is emerging evidence that serum 25(OH)D concentrations
>150 nmol/L (>60 ng/mL) are associated with potential adverse eects [99,100].
Multiple factors, including environmental and genetic determinants and their interactions, account
for variation in serum 25(OH)D levels and health consequences. The main source of vitamin D is
cutaneous biosynthesis induced by skin exposure to UVB light from the sun. Thus, baseline levels of
serum 25(OH)D can vary significantly according to both seasonal and geographical variations, and
are typically lower at the end of winter, especially when living at high latitudes (greater than 37th
parallel north or south of the equator). Indeed, people who live in the far northern and southern
hemispheres often cannot make any vitamin D
3
in their skin for up to 6 months of the year, and are
therefore at relatively greater risk for vitaminD deficiency [
101
,
102
]. However, intake of recommended
dietary allowance (RDA) levels of vitamin D from foods or supplements, as well as established food
fortification programs, such as those in Finland, Sweden, the United States, Canada, and Australia, can
completely compensate for the lack of cutaneous vitamin D biosynthesis due to insucient sunlight
exposure [
102
106
]. More generally, several recommendation-setting bodies have provided guidelines
for the maintenance of optimal vitamin D status and the treatment of vitamin deficiency, suggesting
that
75 nmol/L (
30 ng/mL) is the optimal baseline 25(OH)D concentration to be maintained during
the year through adequate dosage regimens of vitamin D intake from food or supplements, in order to
prevent a drop below 50 nmol/L due to seasonal and geographical influences [99].
Besides seasonal, geographic, and lifestyle variations, a further factor that impinges on circulating
25(OH)D levels is the skin pigmentation-related eciency of sunlight-induced vitamin D production.
Indeed, high levels of the protective skin-darkening pigment melanin reduce the skin’s ability to
produce vitamin D from sunlight. Consistently, there is evidence that skin color change between
summer and winter predicts seasonal 25(OH)D change [
104
,
107
], as well as that much of the variation
in serum 25(OH)D concentration between racial/ethnic groups may be attributed to skin color [
108
].
Overall, sun exposure, vitamin D intake, demographics, and lifestyle, as well as their potential
interactions, are important determinants of vitamin D status, and could therefore have a significant
impact both on its role in pathophysiological mechanisms and its therapeutic applications.
Regarding genetic determinants, numerous genome-wide association studies (GWAS) have
identified multiple genetic modifiers of vitamin D serum levels and biological eects, including
single-nucleotide polymorphisms (SNPs) in genes coding for key proteins involved in vitamin D
metabolism, transport, and signaling, which could be considered in the clinical management with
vitamin D. In particular, various polymorphisms in genes encoding 7-dehydrocholesterol reductase
(DHCR7, which shunts vitamin D precursors toward cholesterol biosynthesis); cytochrome P450
vitamin D hydroxylases, including CYP2R1 (25-hydroxylase), CYP27B1 (1
α
-hydroxylase), and CYP24A1
(24-hydroxylase); vitamin D binding protein (VDBP, also known as GC globulin); and vitamin D
receptor (VDR) were found to be statistically significantly associated with inter-individual variations in
serum 25(OH)D and 1,25(OH)2D levels, either at baseline or after vitamin D supplementation [
109
,
110
],
as well as with susceptibility to various human diseases [
98
,
110
114
]. More specifically, distinct
randomized controlled trials (RCTs) and systematic reviews/meta-analyses have shown that genetic
variants in CYP2R1 (rs10766197, rs10741657, rs12794714, rs1562902, rs2060793), CYP24A1 (rs2209314,
rs2762939, rs6013897), and VDBP (rs7041, rs4588) are either associated with baseline serum 25(OH)D
levels or modify the ecacy of vitamin D supplementation in increasing such levels [
109
,
110
,
114
116
].
On the other hand, polymorphisms in CYP27B1 (rs703842, rs10877012, rs4646536) and VDR (rs2228570,
rs7975232, rs1544410) were most commonly reported to be associated with health outcomes, including
susceptibility to metabolic, inflammatory, autoimmune, and infectious diseases [98,110112,116].
While further validation studies with large sample sizes and controlled confounding factors
are still needed, these findings point to a potential interplay between vitamin D deficiency and
Antioxidants 2020,9, 327 7 of 22
polymorphisms in vitamin D-related genes, suggesting important implications for achieving optimal
vitamin D status and health outcomes in individuals with dierent genetic backgrounds.
Overall, genetic and nongenetic determinants of vitamin D status are significant predictors of
its health outcomes, and may have an important impact on susceptibility to various human diseases.
Indeed, there is already clear evidence that both seasonal variations and genetic modifiers of vitamin D
metabolism and functions are independently associated with inter-individual variability with regard
to the risk of developing cardiovascular disorders, including severe cerebrovascular diseases [
117
,
118
],
as described in more detail below.
5. Vitamin D Deficiency and its Impact on Cerebrovascular Diseases
It is noteworthy that a meta-analysis of pooled data from 32 studies recently found that serum
25(OH)D concentrations <30 ng/mL were associated with higher all-cause mortality than concentrations
>30 ng/mL [
119
]. Specifically, despite some conflicting results, there is evidence that low solar UVB
exposure and low serum 25(OH)D levels are associated with an increased risk of CVD, as well
as that CVD mortality is about double in older individuals with deficient 25(OH)D concentrations
compared with age-matched individuals with adequate 25(OH)D concentrations (>30 ng/mL) [
120
124
].
Indeed, accumulating evidence suggests that vitamin D insuciency or deficiency may adversely
aect the cardiovascular system through multiple eects. Levels of the pro-hormone cholecalciferol
are maintained either through dietary consumption or epidermal synthesis following exposure to
ultraviolet light [
125
]. Nonetheless, “vitamin D insuciency”, defined as 20–29 ng/mL of serum
25(OH)D, is endemic in humans, with more than a billion people aected worldwide, and may
require public health actions, such as systematic vitamin D food fortification [
106
,
126
]. Moreover,
“vitamin D deficiency” (<20 ng/mL) is prevalent in almost half of the healthy population of developed
countries [
126
,
127
], is common in patients with CVD [
127
], and is independently associated with a
higher risk for future cardiovascular events [
126
,
128
]. Furthermore, vitamin D deficiency is likely to
be associated with advanced age, darker skin pigmentation, less sunlight exposure, and low dietary
intake of vitamin D [
129
], and has been linked to an increased risk of age-related morbidities that
include neurodegenerative diseases and cerebrovascular dysfunctions [130132].
Epidemiological evidence suggests an association of vitamin D insufficiency with endothelial
dysfunction in healthy and pathological conditions [
133
,
134
]. Indeed, calcitriol acts as a direct
transcriptional regulator of endothelial nitric oxide (NO) synthase (eNOS), and can promote
normalization of eNOS mRNA expression and enzymatic activity in experimental atherosclerosis [
135
].
Mice carrying mutated, functionally inactive VDR exhibit increased arterial stiness, endothelial
dysfunction, and lower NO bioavailability due to reduced eNOS expression [
136
]. Mice with
endothelial-specific deletion of the VDR exhibit reduced eNOS expression, impaired endothelium-
dependent vasorelaxation, and an augmented pressor eect of angiotensin II [
137
]. Furthermore,
vitamin D can exert powerful immunomodulatory actions to modify the immune response to injury
during various diseases, including atherosclerosis [
64
,
138
], cancer [
25
], asthma [
139
], and stroke [
50
].
In particular, vitamin D can attenuate inflammatory responses and promote protein homeostasis
via modulating the NF-
κ
B and unfolded protein response (UPR) pathways, respectively [
140
,
141
].
In addition, vitamin D can regulate matrix homeostasis through the modulation of distinct matrix
metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) [
142
], consistent with its
deficiency being critical in major cerebrovascular diseases, including brain aneurysms, cerebrovascular
malformations, and stroke, where matrix destabilization is significant [
118
,
143
,
144
]. Overall, it is
plausible that the impaired endothelial function that may accompany low circulating vitamin D levels
contributes to an increased risk of cerebrovascular diseases and mortality. Indeed, there is increasing
interest in how vitamin D levels might influence the onset and severity of cerebrovascular diseases,
including stroke [145150] and cerebrovascular malformations [43,95,117,128,151,152].
Antioxidants 2020,9, 327 8 of 22
5.1. Vitamin D Deficiency and Stroke
Stroke is a crippling cardiovascular event that accounts for 5–10% of all deaths, and is the leading
cause of serious long-term disability, with >50% of survivors discharged into care [
153
]. About 85%
of strokes are caused by a clot formed in a cerebral artery in which a dysfunctional endothelium
would be typically present [
153
,
154
]. Vitamin D deficiency is particularly frequent in people who
have suered a stroke, which is commonly associated with advanced age, limited mobility, decreased
sunlight exposure, and higher prevalence of malnutrition [
155
]. Meta-analyses have found that a
low vitamin D level contributes to a ~50% increased risk of incident stroke [
156
], and that there is a
stepwise increase in stroke risk with decreasing plasma vitamin D level [145].
Clinical vitamin D status appears to influence the incidence, impact, and recovery from ischemic
stroke. Vitamin D deficiency was recently found to be a risk factor for incident stroke, and the
strength of this association does not appear to dier by race [
157
,
158
]. Strikingly, in a prospective
study of 58,646 healthy adults with median follow-up period of 19.3 years, vitamin D intake was
inversely associated with the risk of mortality from stroke [
159
]. Furthermore, low serum levels of
vitamin D at admission have been proposed as an independent prognostic biomarker for greater stroke
severity [
160
,
161
], a larger infarct volume in the acute phase [
162
], a poorer functional outcome at
discharge [
160
,
161
], a higher incidence of cognitive impairment at one month [
150
], a higher risk of
death at one or two years [
160
,
163
], and a greater risk of early recurrent stroke [
149
,
163
]. There is
also evidence that high circulating levels of vitamin D are associated with less cognitive impairment
among stroke patients, manifested as greater functional improvement during rehabilitation [
147
,
164
].
The relationship between plasma vitamin D levels and functional outcome from stroke also applies
to patients who have received intravenous thrombolysis [
148
], consistent with the possibility that
improving vitamin D status after stroke might provide benefits in addition to those from reperfusion.
In a prospective population-based study of >9300 participants, an association was found between
vitamin D and prevalent stroke, but only severe vitamin D deficiency was associated with incident
stroke, with the authors concluding that lower vitamin D levels may not lead to a higher stroke risk,
but may instead be a consequence of stroke [165].
Furthermore, there is evidence that a sucient level of vitamin D could exert several
neuroprotective actions, including reduction of oxidative stress [
166
], regulation of neuronal
inflammation and death from stroke [
50
], and fewer neurogenerative disorders [
167
]. These findings
raise the possibility that low vitamin D serum levels, a treatable risk factor, might be targeted for
the reduction of disability among stroke suerers. Indeed, a study to assess the long-term eect
of supplementation of vitamin D in ischemic stroke patients with low vitamin D levels found a
significant improvement in the outcome after three months [
168
]. Nevertheless, the value of vitamin D
supplementation in preventing stroke is still unclear, as a recent meta-analysis of randomized clinical
trials conducted in more than 80,000 patients found no clinical benefit of vitamin D supplementation in
reducing the incidence of (as opposed to outcome from) major cardiovascular events, including stroke
and cardiovascular death [
169
]. Therefore, it is possible that vitamin D supplementation is less eective
for preventing cardiovascular events than for limiting post-stroke injury and improving outcome.
5.2. Vitamin D Deficiency and CCM Disease
Cerebral cavernous malformation (CCM), also referred to as cavernous angioma or cavernoma, is
a significant vascular disease of genetic origin. CCM lesions mostly occur within the central nervous
system, and involve closely clustered, abnormally dilated and leaky capillaries, which are characterized
by a thin endothelium devoid of normal vessel wall components [
43
,
170
]. These lesions have a
prevalence of 0.5% in the general population, and can be detected by magnetic resonance imaging
(MRI) as single or multiple mulberry-like vascular sinusoids of varying size and locations. Most CCM
lesions are clinically and biologically inactive; however, in 30% of cases, they result in various clinical
symptoms, including focal neurological deficits, recurrent headaches, stroke, intracerebral hemorrhage
(ICH), and seizures. Clinical presentation can occur at any age and at varying levels of severity.
Antioxidants 2020,9, 327 9 of 22
Genetic studies in CCM patient cohorts have led to the identification of three disease genes,
CCM1/KRIT1,CCM2, and CCM3, which have been implicated in all major mechanisms of vascular
integrity maintenance and endothelial barrier function, including the coordination of redox signaling
and autophagy governing cell homeostasis and stress responses [
43
,
171
180
]. Consistent with such
pleiotropic functions, accumulated evidence from animal models and patient cohorts has demonstrated
that loss-of-function mutations of CCM genes only predispose to the development of CCM disease.
CCM may eventually occur with incomplete penetrance and highly variable expressivity, depending on
additional local factors, such as oxidative stress, inflammation, and sensitivity to stress [
43
,
118
,
180
,
181
].
Vitamin D deficiency is one of the risk factors that may impact the susceptibility to local oxidative
stress and inflammation, and thereby health outcomes for vulnerable carriers of mutations in CCM genes.
Indeed, whereas meta-analyses of general observational studies have consistently associated vitamin D
deficiency with an increased risk for inflammatory and CVDs [
120
,
182
186
], specific epidemiological
studies have shown that vitamin D serum levels, including throughout their seasonal variation,
are negatively associated with risk for CCM disease onset and severity [
117
,
151
,
152
]. Moreover,
a genome-wide association study (GWAS) in a large cohort of CCM patients sharing a common founder
mutation in the KRIT1 gene (Q455X) identified a correlation between CCM disease severity and SNPs
in genes involved in vitamin D metabolism and function, including CYP and MMP family members.
This suggested that SNPs in these genes can act as genetic susceptibility factors and modifiers of
CCM disease penetrance and expressivity [
118
]. In particular, CYP27A1 and CYP27B1, two essential
players in the vitamin D signaling system [
187
,
188
], were among the putative genetic modifiers of the
CYP family that appear to influence interindividual dierences in the susceptibility to develop the
most severe disease phenotypes [
118
]. Furthermore, whereas various vascular protective actions of
vitamin D have been shown [
27
,
120
,
128
], an unbiased screening strategy for identifying repurposed
drugs for CCM disease treatment has led to the discovery of vitamin D as a major preventive and
therapeutic candidate, along with tempol (a scavenger of superoxide) [
95
]. In particular, as both
compounds were eective in decreasing cerebrovascular lesion burden in a mouse model of CCM
disease by
50%, it was suggested that their eectiveness was related to their shared ability to
promote endothelial stability through specific antioxidant, anti-inflammatory, and pro-autophagic
activities [
43
,
95
,
128
,
173
175
]. Indeed, as mentioned above, vitamin D can enhance endothelial barrier
function and inhibit peripheral vascular diseases by stimulating autophagy and limiting oxidative stress
and inflammatory events, including the production of ROS, lipopolysaccharides, and inflammatory
cytokines [27,35,93,94,128,189,190].
Thus, the emerging evidence indicates that defective autophagy and redox imbalance play a
major role in the genesis and progression of CCM lesions [
43
,
175
,
180
], as well as that vitamin D exerts
significant protective eects by counteracting such pathogenetic mechanisms [
43
,
95
,
174
,
175
]. Taken
together, these findings suggest that vitamin D should be considered within the recently proposed drug
combination therapy approaches aimed at gaining additive or synergistic eects for a more eective
treatment of CCM disease and associated comorbidities [180,191,192].
6. Conclusions and Perspectives
There is now considerable evidence that, besides regulating calcium homeostasis, vitamin D
influences other fundamental biological processes, such as autophagy, mitochondrial function, redox
homeostasis and signaling, epigenetic changes, and oxidative stress and inflammatory responses.
Serum vitamin D levels, as well as polymorphisms in VDR and CYP enzymes involved in the three
main steps of vitamin D metabolism (25-hydroxylation, 1
α
-hydroxylation, and 24-hydroxylation) [
2
],
have been increasingly associated with the incidence of various human diseases, including cancer and
inflammatory, autoimmune, and neurodegenerative diseases, as well as CVDs [
35
,
98
,
116
,
193
] This is
consistent with findings in VDR- and 1α-hydroxylase-deficient mice [194].
This review has focused on two of the major cerebrovascular diseases that are demonstrably
connected to vitamin D deficiency: stroke and CCM disease. We have highlighted underlying
Antioxidants 2020,9, 327 10 of 22
pleiotropic pro-oxidant and pro-inflammatory molecular mechanisms, as well as the likely importance
of maintaining an optimal vitamin D homeostasis for mitigating the inflammation–oxidative stress
cycle that may exacerbate these cerebrovascular diseases (Figure 3). Indeed, while vitamin D deficiency
is endemic in the population, it is easy to screen for and can be readily and inexpensively treated by
dietary supplementation and modest sunlight exposure. In particular, whereas a low serum level of
vitamin D is associated with higher risk of stroke and negatively impacts recovery and mortality from
stroke, preclinical data suggest that acute administration of vitamin D can limit infarct progression by
modulating post-stroke brain inflammation. Moreover, whereas it is now established that vitamin
D modulates endothelial homeostasis and barrier function [
128
], a potential benefit of vitamin D
in preventing or limiting the onset and severity of CCM disease has clearly emerged from both
epidemiological studies and animal models [43,95,117,151,152].
Antioxidants 2020, 9, x FOR PEER REVIEW 10 of 21
inexpensively treated by dietary supplementation and modest sunlight exposure. In particular,
whereas a low serum level of vitamin D is associated with higher risk of stroke and negatively
impacts recovery and mortality from stroke, preclinical data suggest that acute administration of
vitamin D can limit infarct progression by modulating post-stroke brain inflammation. Moreover,
whereas it is now established that vitamin D modulates endothelial homeostasis and barrier function
[128], a potential benefit of vitamin D in preventing or limiting the onset and severity of CCM disease
has clearly emerged from both epidemiological studies and animal models [43,95,117,151,152].
Figure 3. Vitamin D deficiency and its impact on cerebrovascular diseases. Vitamin D deficiency may
adversely affect endothelial cell function and vascular homeostasis through pleiotropic pro-oxidant
and pro-inflammatory effects, including the downregulation of autophagy, unfolded protein
response (UPR), endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1), and tissue inhibitors of
metalloproteinases (TIMPs), as well as the upregulation of NADPH oxidases (NOXs), reactive oxygen
species (ROS), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inflammatory
cytokines, and matrix metalloproteinases (MMPs). In turn, these effects can promote pro-oxidant and
pro-inflammatory conditions, as well as an enhanced tissue sensitivity to oxidative stress and
inflammatory events, with consequent increased susceptibility to the onset and severity of
cerebrovascular diseases, including stroke and cerebral cavernous malformation (CCM) disease (see
text for details).
On the other hand, the therapeutic effect of vitamin D supplementation remains controversial,
as there is still some inconsistency in the conclusions of distinct RCTs and meta-analyses concerning
its beneficial effects on oxidative stress biomarkers and CVD outcomes, including stroke, or on
mortality [25,119,159,161,168,169,195–199]. Such controversy is akin to that regarding the putative
beneficial effects of antioxidants in optimizing health [200], with the reported discrepancies likely
due to the complexity of the systems and existence of multiple confounding factors. Indeed, a careful
analysis of existing RTC and related meta-analysis studies on the effects of vitamin D
supplementation reveals several methodological limitations, including the use of diverse study
Figure 3.
Vitamin D deficiency and its impact on cerebrovascular diseases. Vitamin D deficiency may
adversely aect endothelial cell function and vascular homeostasis through pleiotropic pro-oxidant and
pro-inflammatory eects, including the downregulation of autophagy, unfolded protein response (UPR),
endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1), and tissue inhibitors of metalloproteinases
(TIMPs), as well as the upregulation of NADPH oxidases (NOXs), reactive oxygen species (ROS), nuclear
factor kappa-light-chain-enhancer of activated B cells (NF-
κ
B), inflammatory cytokines, and matrix
metalloproteinases (MMPs). In turn, these eects can promote pro-oxidant and pro-inflammatory
conditions, as well as an enhanced tissue sensitivity to oxidative stress and inflammatory events, with
consequent increased susceptibility to the onset and severity of cerebrovascular diseases, including
stroke and cerebral cavernous malformation (CCM) disease (see text for details).
On the other hand, the therapeutic eect of vitamin D supplementation remains controversial,
as there is still some inconsistency in the conclusions of distinct RCTs and meta-analyses concerning
its beneficial eects on oxidative stress biomarkers and CVD outcomes, including stroke, or on
mortality [
25
,
119
,
159
,
161
,
168
,
169
,
195
199
]. Such controversy is akin to that regarding the putative
Antioxidants 2020,9, 327 11 of 22
beneficial eects of antioxidants in optimizing health [
200
], with the reported discrepancies likely due
to the complexity of the systems and existence of multiple confounding factors. Indeed, a careful
analysis of existing RTC and related meta-analysis studies on the eects of vitamin D supplementation
reveals several methodological limitations, including the use of diverse study populations, dierent
doses of vitamin D with or without Ca
2+
, dierent durations of supplementation and follow-up,
dierent baseline and acquired circulating 25(OH)D concentrations, and dierent study outcome
parameters [
99
,
201
]. Furthermore, significant discrepancies could result from the large inter-individual
variation in genetic determinants of the ecacy of vitamin D supplementation [
12
,
109
,
110
], as well
as its context-dependent eects on mechanisms in endothelial cells, including autophagy [
202
].
Consistent with these potential shortcomings in evaluating the eects of vitamin D supplementation,
there remains much controversy and an open debate about the reliability of either RCTs or their
meta-analyses [99,203,204].
In contrast, the outcomes of a large number of experimental studies have consistently shown
that vitamin D influences most of the risk factors and molecular mechanisms associated with CVDs,
suggesting that its use in the clinical setting should be considered for the prevention of the onset,
progression, and severity of these diseases.
In conclusion, while the benefit of vitamin D supplementation on cerebrovascular outcome
requires deeper study, it may represent a novel approach for limiting the overall impact of acute stroke
and CCM disease. Therefore, we suggest that it is now essential both to implement accurate screenings
and large, well-powered RCTs for investigating vitamin D deficiency and supplementation in stroke
and CCM patients, in order to more fully characterize the molecular mechanisms underlying the
eects of vitamin D. In particular, a better understanding of the emerging major role of autophagy in
the multiple health-promoting eects of vitamin D [
28
] is needed, as well as the role of factors that
influence the activity of CYP vitamin D-metabolizing hydroxylases and local production of vitamin D’s
hormonally active form, calcitriol [
1
,
2
]. Such knowledge may lead to the design of drug combinations
and multitargeting therapeutic strategies for the more eective treatment of diseases associated with
vitamin D deficiency.
Author Contributions:
Conceptualization, S.F.R.; writing—original draft preparation, H.A.K., A.P., A.R., F.R.,
C.G.S., and S.F.R.; writing—review and editing, S.F.R., C.G.S., A.P., A.R., T.M.D.S.; figure preparation–Figure 1,
H.A.K. and C.G.S., Figures 2and 3, A.P. and S.F.R.; supervision, S.F.R. All authors have read and agreed to the
published version of the manuscript.
Funding:
This work was supported by the Telethon Foundation (grant GGP15219 to S.F.R.), the Fondazione CRT
(Cassa di Risparmio di Torino) (project grant “Cerebro-NGS.TO” to S.F.R.), and the Universit
à
degli Studi di
Torino (Local Research Funding 2016-19 to SFR).
Acknowledgments:
The authors are grateful to CCM Italia, the Italian Research Network for Cerebral Cavernous
Malformation (https://www.ccmitalia.unito.it), and the Associazione Italiana Angiomi Cavernosi (AIAC) Onlus
(https://www.aiac.unito.it), including its president Massimo Chiesa, for fundamental support, and Santina Barbaro
for helpful collaboration. The authors also thank Nicola Retta for his kind help in the realization of the figures.
This article is dedicated to the memory of Rosa Giunta and Fortunato Barbaro.
Conflicts of Interest: The authors declare no conflict of interest.
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... Most neurovascular risk factors, both traditional and newly identified, are linked to endothelial dysfunction in a cumulative manner, such as vitamin D deficiency. Vitamin D insufficiency has been associated to major chronic diseases such as cardiovascular and neurological disorders, diabetes, and cancer, all of which are linked to oxidative stress, inflammation, and aging [22]. It would be beneficial to identify clinical or biological markers related to the cardiovascular system (inflammation, excitotoxicity, endothelial and atrial dysfunction biomarkers), as well as risk factors that could become therapeutic targets for the prevention of wake-up stroke, resulting in lower mortality and disability in the medium to long term. ...
... The impact of vitamin D deficiency in cerebrovascular diseases may adversely affect endothelial cell function and vascular homeostasis through pleiotropic pro-oxidant (endothelial nitric oxide synthase (eNOS), reactive oxygen species (ROS), upregulation of NADPH oxidases (NOXs)) and pro-inflammatory effects (inflammatory cytokines, nuclear factor kappa-lightchain-enhancer of activated B cells (NF-B), matrix metalloproteinases (MMPs)). In turn, these effects related to vitamin D deficiency can enhance tissue sensitivity to oxidative stress and inflammatory events, with consequent increased susceptibility to the onset and severity of stroke events [22]. ...
... We have found that serum vitamin D levels may be associated with an increased risk of wakeup IS, in particular serum vitamin D levels ≤9 ng/ml multiply by 15 the risk of suffering an ischemic stroke during sleep. The cardiovascular system is known to be particularly sensitive to vitamin D levels, which can lead to endothelial dysfunction and vascular abnormalities through a variety of mechanisms, including cytokine release, superoxide migration inhibition, and monocyte adhesion and migration [22]. Taking into account that one of the physiological mechanisms involved to wakeup stroke is the endothelial dysfunction, we hypothesized that the endothelial dysfunction could be the "meeting point", and the endothelium could be the link between risk factors and vascular lesion due vitamin D deficiency. ...
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Background: Wake-up ischemic stroke (IS) has been usually excluded from acute stroke therapy options for being outside of the safe treatment window. We identified risk factors, and clinical or molecular biomarkers that could be therapeutic targets for wake-up stroke prevention, thus hopefully leading to a decrease in its mortality and disability in medium to long-term outcome. Methods: 4251 ischemic stroke (IS) patients from a prospectively registered database were recruited; 3838 (90.3%) had known onset-symptom time, and 413 (9.7%) were wake-up strokes. The main endpoint was to analyze the association between different serum biomarkers with wake-up IS episodes and their progression. Leukocytes count, serum levels of C-reactive protein, fibrinogen, interleukin 6 (IL-6), and vitamin D were analyzed as inflammation biomarkers; N-terminal pro-B-type Natriuretic-Peptide and microalbuminuria, used as atrial/endothelial dysfunction biomarkers; finally, glutamate levels as excitotoxicity biomarker. In addition, demographic, clinical and neuroimaging variables associated with the time-evolution of wake-up IS patients and functional outcome at 3 months were evaluated. Good and poor functional outcome were defined as mRS ≤2 and mRS > 2 at 3 months, respectively. Results: Wake-up IS showed a poorer outcome at 3-months than in patients with known on-set-symptom time (59.1% vs. 48.1%; p < 0.0001). Patients with wake-up IS had higher levels of inflammation biomarkers; IL-6 levels at admission (51.5 ± 15.1 vs. 27.8 ± 18.6 pg/ml; p < 0.0001), and low vitamin D levels at 24 h (5.6 ± 5.8 vs. 19.2 ± 9.4 ng/ml; p < 0.0001) are worthy of attention. In a logistic regression model adjusted for vitamin D, OR was 15.1; CI 95%: 8.6-26.3, p < 0.0001. However, we found no difference in vitamin D levels between patients with or without clinical-DWI mismatch (no: 18.95 ± 9.66; yes: 17.84 ± 11.77 ng/mL, p = 0.394). No difference in DWI volume at admission was found (49.3 ± 96.9 ml in wake-up IS patients vs. 51.7 ± 98.2 ml in awake IS patients; p = 0.895). Conclusions: Inflammatory biomarkers are the main factors that are strongly associated with wake-up IS episodes. Wake-up IS is associated with lower vitamin D levels. These data indicate that vitamin D deficiency could become a therapeutic target to reduce wake-up IS events.
... Among the pleiotropic effects of loss of KRIT1 function, growing evidence has accumulated over the past decade providing strong support for a major implication of alterations in key redox-dependent mechanisms involved in cellular homeostasis and defenses against oxidative stress and inflammation, including autophagy and signaling pathways mediated by redox-sensitive transcription factors and regulatory enzymes, such as FoxO1, c-Jun, NF-κB, Nrf2, and PKC [15][16][17]19,23,83]. Consistently, distinct pathological phenotypes associated with loss of KRIT1 function in experimental models could be prevented or rescued by either targeted antioxidant enzymes or potential pharmacological compounds endowed with antioxidant, anti-inflammatory and/or proautophagic activities, such as Tempol, vitamin D, rapamycin, and avenanthramides; thus, providing further support to a key contribution in oxy-inflammatory mechanisms [10,12,14,17,19,22,[84][85][86][87][88]. ...
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KRIT1 loss-of-function mutations underlie the pathogenesis of Cerebral Cavernous Malformation (CCM), a major vascular disease affecting the central nervous system (CNS). However, KRIT1 is also expressed outside the CNS and modulates key regulators of metabolic and oxy-inflammatory pathways, including the master transcription factor FoxO1, suggesting a widespread functional significance. Herein, we show that the KRIT1/FoxO1 axis is implicated in liver metabolic functions and antioxidative/antiglycative defenses. Indeed, by performing comparative studies in KRIT1 heterozygous (KRIT1−/−) and wild-type mice, we found that KRIT1 haploinsufficiency resulted in FoxO1 expression/activity downregulation in the liver, and affected hepatic FoxO1-dependent signaling pathways, which are markers of major metabolic processes, including gluconeogenesis, glycolysis, mitochondrial respiration, and glycogen synthesis. Moreover, it caused sustained activation of the master antioxidant transcription factor Nrf2, hepatic accumulation of advanced glycation end-products (AGEs), and abnormal expression/activity of AGE receptors and detoxifying systems. Furthermore, it was associated with an impairment of food intake, systemic glucose disposal, and plasma levels of insulin. Specific molecular alterations detected in the liver of KRIT1−/− mice were also confirmed in KRIT1 knockout cells. Overall, our findings demonstrated, for the first time, that KRIT1 haploinsufficiency affects glucose homeostasis and liver metabolic and antioxidative/antiglycative functions, thus inspiring future basic and translational studies.
... Gatto [41] investigated the effect of VDR and FokI polymorphism in 190 PD patients suggesting a link with cognitive decline (p = 0.005). In the study by Kim et al. [42], Vit D levels were associated with the degree of olfactory impairment in 39 PD patients, as evidenced by a reduced odor identifica-tion score (β = 0.38, p < 0.01). The serum VitD level was also negatively correlated with the score for item number 28 on the Non-Motor Symptoms Scale for PD (NMSS) (Spearman's rho = -0.32, ...
... Significantly vitamin D rise the total antioxidant capacity [110]. ...
... Vitamin D3 potent vitamin in several physiological metabolisms present in regulated bone metabolism and secretion of parathyroid hormone and devise immunity beside the critical antioxidant roles including inducing lipid peroxidation in the cell membrane and keeping membrane structure, diminishing the ROS formation in a vascular complication that occurs in diabetes and CVD diseases. Significantly vitamin D rise the total antioxidant capacity in a variety of metabolic enzymes [34]. Tocopherol (vitamin E) is naturally found in eight forms including alpha, beta, gamma, delta, portions of tocopherol, and tocotrienol [8]. ...
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Background: Cinnamomum zeylanicum Nees) (Lauraceae) is used as a spicy culinary herb in the conventional Eastern. Cinnamon bark is a rich part in phytochemical compounds and bioactive phenolic compounds and vitamins are constituted a therapeutic chemical composition. Extract of cinnamon bark was identified as a potent source of antioxidants, anti-inflammatory compounds. Aim: detection of the qualitative and quantitative various antioxidant compounds from C. zeylanicum barks using Classical extraction and HPLC methods. Methodology: water and ethanol extract preparation from Cinnamon bark powder at ratio (1:10). Different experimental methods have been used to indicated phytoconstituent in cinnamon water extract, used various chemical reagents. HPLC methods were used to quantify the phenols and vitamins in cinnamon extract barks. Results: the qualitative detection of phytochemical compounds in cinnamon water extract showed the presence of saponins, steroids, alkaloids, phenols, tannins, flavonoids, Coumarins, and Resins. Quantifications detection of trace elements (Zn, Se, Cu, Fe, Mn, Co, V, Ni, Mo) help of keep oxidative/antioxidant balance in mammals organisms. The study investigated that cinnamaldehyde and eugenol are major phenolic compounds that may be responsible for the observed antioxidant activity in water extract of cinnamon barks.The result showed a variety of phenolic compounds (quercetin, gallic acid, rutin, kaempferol, lignin, and pyrogallol) that have antioxidant activity and anti-inflammatory in different mechanisms. Vitamins appear interesting results by the indicated concentration of fat-soluble vitamins (A, E, D, K) and water-soluble vitamins (C, B1, B2) in water extract and ethanol extract of bark. Conclusion: Cinnamomum zeylanicum bark has bioactive compounds responsible for antioxidant, antidiabetic, and anti-inflammatory activity. Therefore, considered a traditional medical plant to prevent disease, and should investigation for more cinnamon properties be conducted on this abundant plant which acts as a natural source of alternative medical drugs.
... Significantly vitamin D rise the total antioxidant capacity [110]. ...
... In addition to regulating calcium and phosphorus metabolism, VD with hormone properties can induce cell differentiation and apoptosis, inhibit cell proliferation and other cell signal transduction processes, participate in the regulation process of multiple genes, and involve in the physiological and pathological mechanism of various diseases [1,2]. VD deficiency is related to many diseases, including immune dysfunction, metabolic syndrome, insulin resistance, infection, cancer, and cardiovascular abnormalities [3][4][5]. According to statistics, about 30% and 60% of children and adults in the world are Open Access † Fubin Qiu and Rui Li contributed equally to this work *Correspondence: 13835190191@126.com ...
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Abstract Background Iron and vitamin D (VD) is essential to health. Previous studies have shown that iron homeostasis has a potential effect on VD metabolism, but the mechanism is not fully understood. Objectives To explore the relationship between VD metabolism and iron metabolism, as well as the regulatory mechanism of iron on VD metabolism. Methods 40 male rats were fed adaptively for 7 days and randomly divided into control (C, n = 6 normal diet) group and model (M, n = 24 iron deficient diet) by simple randomization, the latter was used to establish iron deficiency anemia (IDA) model. After 6 weeks of feeding, the M group was randomly divided into: iron deficiency group (DFe), low iron group (LFe), medium iron group (MFe) and high iron group (HFe) by block randomization. Different doses of iron dextran (based on iron content (100 g·bw·d)): 0, 1.1, 3.3 and 9.9 mg) were given respectively. After 4 weeks, the rats were anesthetized with 8% chloral hydrate, Blood (collected from the abdominal aorta), liver and kidney tissues were collected. The serum and tissues were separately packed and frozen at -80℃ for testing. Results The results showed that the levels of hemoglobin (Hb), red blood cell (RBC), serum iron (SI), liver iron, and kidney iron in DFe group were lower than those in the other four groups, while the levels of total iron-binding capacity (TIBC), transferrin (TF) and transferrin receptor (Tfr) in DFe group were higher than those in other groups; The serum levels of 25-(OH)D3 and 1,25-(OH)2D3 in DFe group were significantly lower than those in C group (P
... [1][2][3][4] Vitamin D deficiency has also been linked to increased incidence and severity of multiple diseases such as infections, diabetes, cardiovascular disease, autoimmune diseases such as inflammatory bowel disease and multiple sclerosis, and cancer. [5][6][7][8][9][10] Unfortunately, vitamin D inadequacy is a major public health problem worldwide, even in low-latitude countries. [11][12][13][14] The main source of vitamin D is endogenous cutaneous synthesis through exposure to solar ultraviolet B radiation. ...
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Introduction Vitamin D is critical for bone health and its deficiency has been linked to increased incidence and severity of multiple diseases. Even so, vitamin D inadequacy is a major public health problem worldwide. The main source of vitamin D is endogenous cutaneous synthesis through exposure to solar ultraviolet B radiation, which is influenced by several factors, including occupational. The active duty Navy military personnel may be prone to vitamin D inadequacy, but a worldwide overview of vitamin D status in this specific population is still lacking. Methods and analysis The CoCoPop mnemonic will be used for determining the inclusion criteria. Scopus, Web of Science and PubMed/Medline will be searched for all studies including 25-hydroxyvitamin D concentrations of the active duty Navy military personnel. Data extraction and quality assessment (Joanna Briggs Institute’s and Downs and Black checklists) will be performed by two reviewers and data will be synthesised in narrative, tabular and map formats. Ethics and dissemination This study will not involve human or animal subjects and, thus, does not require ethics approval. The outcomes will be disseminated via publication in a peer-reviewed scientific journal and presentation at a scientific conference. PROSPERO registration number CRD42022287057.
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Background Previous observational studies have supported the hypothesis that vitamin D supplementation protects against stroke. However, several current intervention studies contradict this observation. Therefore, we conducted a meta-analysis to investigate further the association between vitamin D supplementation and the risk of stroke. Methods This meta-analysis was conducted in accordance with the PRISMA statement and included all the randomized controlled trials (RCTs) that analyzed the relationship between vitamin D supplementation and the risk of stroke. A literature search strategy was established, and the following Medical Search Terms (MeSH) were used: “vitamin D,” “Calcitriol,” “Calcifediol,” “Cholecalciferol,” “25-Hydroxyvitamin D 2,” “ergocalciferols,” “stroke,” and stroke-derived terms. We searched for articles published before January 2022 in several databases, namely, PubMed, Web of Science, EMBASE, and The Cochrane Library. We also reviewed references included in relevant published meta-analyses and searched the http://www.ClinicalTrials.gov website for additional RCTs. The Q test and I ² were utilized to assess the degree of heterogeneity among the studies. Review Manager 5.3 and STATA16.0 software programs were used to assess the literature quality and perform statistical analyses. Results In total, twenty-four RCTs (86,202 participants) were included. There was no statistical heterogeneity among the RCTs ( I ² = 0.0%, P = 0.94) included in this meta-analysis. We determined that vitamin D supplementation was not associated with a reduced risk of stroke compared with the placebo (RR = 1.02, 95% CI: 0.93–1.13, P = 0.65). In total, 10 studies only included women, and 14 studies included women and men among the 24 RCTs. Therefore, we performed a subgroup analysis based on sex. After the subgroup analysis, the effect remained statistically insignificant (mixed-sex group: RR = 1.06, 95% CI: 0.93–1.22, P = 0.37, women group: RR = 0.98, 95% CI: 0.86–1.13, P = 0.80). The results were generally comparable, based on age, body mass index (BMI), follow-up period, baseline 25-hydroxyvitamin D (25(OH)D) levels, the designated endpoint, latitude, vitamin D dosage, type of vitamin D administered, and an absence or presence of concurrent calcium supplementation ( P > 0.05). Conclusion Our study revealed that additional vitamin D supplementation did not reduce the risk of stroke. Therefore, additional RCTs of similar design should not be encouraged to assess any association between vitamin D supplementation and reduced stroke risk.
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Dicarbonyl stress is a dysfunctional state consisting in the abnormal accumulation of reactive α-oxaldehydes leading to increased protein modification. In cells, post-translational changes can also occur through S-glutathionylation, a highly conserved oxidative post-translational modification consisting of the formation of a mixed disulfide between glutathione and a protein cysteine residue. This review recapitulates the main findings supporting a role for dicarbonyl stress and S-glutathionylation in the pathogenesis of cerebrovascular diseases, with specific emphasis on cerebral cavernous malformations (CCM), a vascular disease of proven genetic origin that may give rise to various clinical signs and symptoms at any age, including recurrent headaches, seizures, focal neurological deficits, and intracerebral hemorrhage. A possible interplay between dicarbonyl stress and S-glutathionylation in CCM is also discussed.
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Enhanced oxidative stress has been associated with muscle mitochondrial changes and metabolic disorders. Thus, it might be a good strategy to decrease oxidative stress and improve mitochondrial changes in skeletal muscle. In the present study, we investigate the role of the most biologically active metabolite of vitamin D, 1,25-dihyroxyvitamin D (1,25(OH)2D) in oxidative stress and mitochondrial changes in tertiary butyl-hydrogen (tBHP)-treated C2C12 muscle cells. Differentiated C2C12 muscle cells were pretreated with tBHP, followed by 1,25(OH)2D for additional 24 h. An exogenous inducer of oxidative stress, tBHP significantly increased oxidative stress, lipid peroxidation, intracellular damage, and cell death which were reversed by 1,25(OH)2D in C2C12 myotubes. 1.25(OH)2D improves tBHP-induced mitochondrial morphological changes such as swelling, irregular cristae, and smaller size and number, as observed by transmission electron microscope. In addition, 1,25(OH)2D treatment increases mtDNA contents as well as gene expression involved in mitochondrial biogenesis such as PGC1α, NRF1, and Tfam. Significant increments in mRNA levels related to antioxidant enzymes such as Nrf2, HMOX1, and TXNRD1, myogenic differentiation markers including myoglobin, muscle creatine kinase (MCK), and MHCІ and ІІ, and vitamin D metabolism such as CYP24, CYP27, and vitamin D receptor (VDR) were found in 1,25(OH)2D-treated myotubes. Moreover, upon t-BHP-induced oxidative stress, significant incremental changes in nicotinamide adenine dinucleotide (NAD) levels, activities of AMP-activated protein kinase (AMPK)/sirtulin 1 (SIRT1), and SIRT1 expression were noted in 1,25(OH)2D-treated C2C12 muscle cells. Taken together, these results suggest the observed potent inhibitory effect of 1,25(OH)2D on muscle oxidative stress and mitochondrial dynamics might be at least involved in the activation of AMPK and SIRT1 activation in muscle cells.
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Loss-of-function mutations of the gene encoding Krev interaction trapped protein 1 (KRIT1) are associated with the pathogenesis of Cerebral Cavernous Malformation (CCM), a major cerebrovascular disease characterized by abnormally enlarged and leaky capillaries and affecting 0.5% of the human population. However, growing evidence demonstrates that KRIT1 is implicated in the modulation of major redox-sensitive signaling pathways and mechanisms involved in adaptive responses to oxidative stress and inflammation, suggesting that its loss-of-function mutations may have pathological effects not limited to CCM disease. The aim of this study was to address whether KRIT1 loss-of-function predisposes to the development of pathological conditions associated with enhanced endothelial cell susceptibility to oxidative stress and inflammation, such as arterial endothelial dysfunction (ED) and atherosclerosis. Silencing of KRIT1 in human aortic endothelial cells (HAECs), coronary artery endothelial cells (HCAECs), and umbilical vein endothelial cells (HUVECs) resulted in increased expression of endothelial proinflammatory adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) and in enhanced susceptibility to tumor necrosis factor alpha (TNF-α)-induced apoptosis. These effects were associated with a downregulation of Notch1 activation that could be rescued by antioxidant treatment, suggesting that they are consequent to altered intracellular redox homeostasis induced by KRIT1 loss-of-function. Furthermore, analysis of the aorta of heterozygous KRIT1+/− mice fed a high-fructose diet to induce systemic oxidative stress and inflammation demonstrated a 1.6-fold increased expression of VCAM-1 and an approximately 2-fold enhanced fat accumulation (7.5% vs 3.6%) in atherosclerosis-prone regions, including the aortic arch and aortic root, as compared to corresponding wild-type littermates. In conclusion, we found that KRIT1 deficiency promotes ED, suggesting that, besides CCM, KRIT1 may be implicated in genetic susceptibility to the development of atherosclerotic lesions.
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In the clinical setting, administration of high daily or bolus doses of vitamin D is often solely based on 25-hydroxyvitamin D [25(OH)D] testing. This review summarizes the evidence of the effect of vitamin D on cardiovascular disease (CVD). Meta-analyses of randomized controlled trials (RCTs) have demonstrated that CVD risk markers, such as lipid parameters, inflammation markers, blood pressure, and arterial stiffness, are largely unaffected by vitamin D supplementation. Similar results have been obtained regarding CVD events and mortality from (meta)-analyses of RCTs, even in subgroups with 25(OH)D concentrations <50 nmol/l. Likewise, Mendelian randomization studies have indicated that the genetic reduction of the 25(OH)D concentration does not increase CVD risk. Some studies do not exclude the possibility of adverse vitamin D effects, such as elevated plasma calcium concentration and an increased CVD risk at a 25(OH)D concentration >125 nmol/l. Based on a conservative benefit-risk management approach, vitamin D doses beyond the nutritionally recommended amounts of 600 to 800 IE daily currently cannot be advised for the prevention of CVD events.
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Objective: To investigate the effect of single nucleotide polymorphisms (SNPs) of the key genes in vitamin D metabolic pathway on the serum 25(OH)D level after long-term vitamin D3 supplementation and provide a theoretical basis for rational vitamin D3 supplementation in diabetic patients with different genetic backgrounds. Methods: Patients with type 2 diabetes (T2DM) who met the inclusive criteria were given 800 IU of vitamin D3 daily for 30 consecutive months. Serum 25(OH)D levels was measured at enrollment and every 6 months after enrollment. The average value of four-time measurements represented individual serum 25(OH)D level during vitamin D3 supplementation. Multiplex TaqMan genotyping was used to determine the distribution of eight candidate SNPs in genes of DHCR7, CYP2R1, CYP27B1, CYP24A1, and VDR, which are key genes in the vitamin D metabolic pathway, in diabetic patients. Results: At baseline, the average serum 25(OH)D level was 22.71 ± 6.87 ng/mL, and 17.9% of patients had a ≥30 ng/mL level. During supplementation, the level of 25(OH)D increased significantly at each time point, and the average 25(OH)D level increased to 30.61 ± 5.04 ng/mL; however, there were 44.6% of patients whose serum 25(OH)D levels were still below 30 ng/mL. In the patients with CYP27B1 (rs10877012) G/T genotype, 71.79% achieved sufficient level of 25(OH)D, which was significantly higher than the other two genotypes (P < 0.05). Compared with those with T/T genotype, the RR of the patients with rs10877012 for <30 ng/mL level was 0.544 (95% CI: 0.291-0.917), and the RR after adjusting age and outdoor activity was 0.560 (95% CI: 0.292-0.970). Conclusion: The serum 25(OH)D level in patients with diabetes mellitus after long-term vitamin D3 supplementation is associated with CYP27B1 polymorphism. Patients with rs10877012 G/T allele have a better response to vitamin D3 supplementation. Trial registration: This trial is registered with ChiCTR-IPC-17012657.
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Background and Purpose— Recent findings suggest that vitamin D, a neuroprotective prohormone, is involved in the pathogenesis of cardiovascular disease. However, previous studies investigating the association between vitamin D and stroke have shown inconsistent findings. In view of these discrepancies, we determined the association of vitamin D status with stroke using data from a population-based study. Methods— Within the RS (Rotterdam Study), an ongoing prospective population-based study, we measured serum 25-hydroxyvitamin D concentrations between 1997 and 2008 in 9680 participants (56.8% women) aged ≥45 years. We assessed a history of stroke at baseline and subsequently followed for incident stroke until January 1, 2016. Regression models were used to investigate the association of serum 25-hydroxyvitamin D with prevalent and incident stroke separately, adjusted for age, sex, study cohort, season of blood sampling, and other cardiovascular risk factors. Results— Of 9680 participants, 339 had a history of stroke at baseline. Serum 25-hydroxyvitamin D concentration was associated with prevalent stroke, adjusted odds ratio per SD decrease, 1.31; 95% CI, 1.14–1.51. After excluding participants with prevalent stroke, we followed 9338 participants for a total of 98 529 person-years. During follow-up, 735 participants developed a stroke. Lower serum 25-hydroxyvitamin D concentration was not associated with a higher stroke risk, adjusted hazard ratio per SD decrease, 1.06; 95% CI, 0.97–1.16. However, severe vitamin D deficiency did show a significant association: hazard ratio, 1.25; 95% CI, 1.05–1.50. Conclusions— In this population-based cohort, we found an association between vitamin D and prevalent stroke. Only severe vitamin D deficiency was associated with incident stroke. This suggests that lower vitamin D levels do not lead to a higher stroke risk but are instead a consequence of stroke.
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Cardiovascular diseases (CVDs) are among the leading threats to human health. The advanced glycation end product (AGE) and receptor for AGE (RAGE) signaling pathway regulates the pathogenesis of CVDs, through its effects on arterial stiffness, atherosclerosis, mitochondrial dysfunction, oxidative stress, calcium homeostasis, and cytoskeletal function. Targeting the AGE/RAGE pathway is a potential therapeutic strategy for ameliorating CVDs. Vitamin D has several beneficial effects on the cardiovascular system. Experimental findings have shown that vitamin D regulates AGE/RAGE signaling and its downstream effects. This article provides a comprehensive review of the mechanistic insights into AGE/RAGE involvement in CVDs and the modulation of the AGE/RAGE signaling pathways by vitamin D.
Chapter
Vitamin D is a principal factor required for mineral and skeletal homeostasis. Vitamin D deficiency during development causes rickets and in adults can result in osteomalacia and increased risk of fracture. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the hormonally active form of vitamin D, is responsible for the biological actions of vitamin D which are mediated by the vitamin D receptor (VDR). Mutations in the VDR result in early-onset rickets and low calcium and phosphate, indicating the essential role of 1,25(OH)2D3/VDR signaling in the regulation of mineral homeostasis and skeletal health. This chapter summarizes our current understanding of the production of the vitamin D endocrine hormone, 1,25(OH)2D3, and the actions of 1,25(OH)2D3 which result in the maintenance of skeletal homeostasis. The primary role of 1,25(OH)2D3 is to increase calcium absorption from the intestine and thus to increase the availability of calcium for bone mineralization. Specific actions of 1,25(OH)2D3 on the intestine, kidney, and bone needed to maintain calcium homeostasis are summarized, and the impact of vitamin D status on bone health is discussed.
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The aim of this study was to investigate the protective effects of vitamin D (VD) against myocardial ischemia‐reperfusion (I/R) injury in hearts. An I/R injury model was induced by left coronary artery ligation in SD rats (in vivo) and Langendorff perfusion of isolated hearts (in vitro). The infarction areas were determined by triphenyltetrazolium chloride (TTC) staining. Changes in the ST segment, cardiac function, lactate dehydrogenase (LDH) activity, creatine kinase (CK) activity, inflammatory cytokine (interleukin‐6 (IL‐6), IL‐1β and tumor necrosis factor‐α (TNF‐α)) levels and the RhoA/ROCK/NF‐ĸB pathway were tested in rats with I/R injury treated with or without VD. VD notably alleviated myocardial injury with decreased infarction areas and had a restorative effect on cardiac function, which was specifically manifested as a restored ST segment, increased myocardial contractility and increased coronary blood flow in the isolated hearts. The levels of CK and LDH were also suppressed by VD. In addition, VD significantly decreased the expression of inflammatory cytokines in rat sera and isolated hearts. The RhoA/ROCK/NF‐κB pathway in I/R‐injured rats was also obviously inhibited with VD treatment. The present study demonstrates that VD plays a protective role against myocardial injury by inhibiting inflammation through repressing the RhoA/ROCK/NF‐κB pathway. This article is protected by copyright. All rights reserved