Literature Review

Role of Platelets in the Development of Atherosclerosis

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DOI: 10.1016/j.tcm.2003.09.007 · Source: PubMed
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Abstract
Platelets are blood cell fragments that originate from the cytoplasm of megakaryocytes in the bone marrow and circulate in blood to play a major role in the hemostatic process and in thrombus formation after an endothelial injury. Recent studies have provided insight into platelet functions in inflammation and atherosclerosis. A range of molecules, present on the platelet surface and/or stored in platelet granules, contributes to the cross-talk of platelets with other inflammatory cells during the vascular inflammation involved in the development and progression of atherosclerosis. This review discusses the nature of these molecules and the mechanisms involved in the participation of platelets in atherosclerosis, with emphasis on P-selectin, platelet-monocyte interactions, chemokines, and inflammatory cytokines.
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PII S1050-1738(03)00169-5 TCM
Role of Platelets in the Development of
Atherosclerosis
Yuqing Huo* and Klaus F. Ley
Platelets are blood cell fragments that originate from the cytoplasm of
megakaryocytes in the bone marrow and circulate in blood to play a
major role in the hemostatic process and in thrombus formation after
an endothelial injury. Recent studies have provided insight into platelet
functions in inflammation and atherosclerosis. A range of molecules,
present on the platelet surface and/or stored in platelet granules, con-
tributes to the cross-talk of platelets with other inflammatory cells
during the vascular inflammation involved in the development and
progression of atherosclerosis. This review discusses the nature of these
molecules and the mechanisms involved in the participation of plate-
lets in atherosclerosis, with emphasis on P-selectin, platelet– monocyte
interactions, chemokines, and inflammatory cytokines. (Trends
Cardiovasc Med 2004;14:1822) n2004, Elsevier Inc.
Platelet Activation in
Atherosclerosis
Platelet activation can be seen in the
different phases of atherosclerosis. De-
tection of activated platelets as defined
by P-selectin surface expression in pe-
ripheral blood of patients with unstable
atherosclerotic disease was first reported
by Fitzgerald et al. (1986). These circu-
lating activated platelets are very likely
to associate with thrombotic events. Cir-
culating activated platelets were also
Yuqing Huo and Klaus F. Ley are at the
Cardiovascular Research Center and Depart-
ment of Biomedical Engineering, University
of Virginia, Health Science Center, Charlot-
tesville, Virginia, USA.
*Address correspondence to: Y. Huo, Car-
diovascular Research Center and Department
of Biomedical Engineering, University of
Virginia, Health Science Center, Box 801394,
Charlottesville, VA 22908, USA. Tel.: (+1) 434-
243-9351; fax: (+1) 434-924-2828; e-mail:
yh3s@virginia.edu.
D2004, Elsevier Inc. All rights reserved.
1050-1738//$-see front matter
18 TCM Vol. 14, No. 1, 2004
detected in the blood of atherosclerotic
rabbits (Tsao et al. 1994) and patients
with stable coronary disease (Furman
et al. 1998). Interestingly, most risk fac-
tors of atherosclerosis—including hyper-
cholesterolemia (Broijersen et al. 1998),
hypertension (Nityanand et al. 1993),
cigarette smoking (Nowak et al. 1987),
and diabetes (Manduteanu et al. 1992)—
are able to increase the number of acti-
vated platelets in circulation. The pres-
ence of circulating activated platelets
preceding massive thrombotic events
such as myocardial infarction or stroke
may be relevant to the development and
progression of atherosclerosis.
The molecular mechanisms responsi-
ble for platelet activation in atherosclero-
sis are unknown. In a thrombotic event,
platelet activation begins with the bind-
ing of adhesive receptors to their ligands
on extracellular matrix constituents
(Ruggeri 2002). This process is further
strengthened by signaling through a
thrombin produced on the membrane of
stimulated platelets, adenosine diphos-
phate (ADP) generated by vascular cells
and stimulated platelets, epinephrine re-
leased in response to stress, and throm-
boxane (TX) A
2
synthesized by stimulated
platelets (Ruggeri 2002). In the early
phase of atherosclerosis, platelet activa-
tion may be attributed to (a) reactive
oxygen species generated by risk factors
of atherosclerosis, including superoxide,
hydroxyl radical, and peroxynitrite; (b)
reduction in endothelial antithrombotic
properties such as production of nitric
oxide, prostacyclin, and CD39, an ecto-
ADPase that degrades ADP; or (c) an
increase in prothrombotic and proin-
flammatory mediators, including tissue
factor and chemokines in the circulation
or immobilized on the endothelium. Ad-
ditionally, following formation of lesions
on the vessel wall, platelet activation may
be initiated by ligation of GPIb with the
endothelial receptor P-selectin and en-
dothelial von Willebrand factor (VWF)
during platelet tethering on intact but
dysfunctional endothelium.
Platelet activation influences the devel-
opment of atherosclerosis. Inhibition of
platelet TX A
2
production by aspirin
(Cyrus et al. 2002) and indomethacin
(Pratico et al. 2001) or TX receptors
(Cayatte et al. 2000) by antagonist is
able to dramatically diminish the forma-
tion of atherosclerotic lesions. Some
conflicting data exist. For example, some
findings did not support a beneficial ef-
fect of aspirin in atherosclerosis (Cayatte
et al. 2000, Napoli et al. 2002). Also, the
inhibitory effect of aspirin in atheroscle-
rosis may be achieved by suppressing
not only platelet cyclooxygenase (COX)-
1, but also COX-2 in macrophages and
smooth muscle cells in the vessel wall.
Interaction of Activated
Platelets with Endothelium
Activated platelets are able to interact
with endothelium of postcapillary ven-
ules in mice with hypercholesterolemia
(Tailor and Granger 2003) or after stim-
ulation with the calcium ionophore
A23187 (Frenette et al. 1995). Consistent
with these studies, using epifluoresence
microscopy, we observed that in vitro-
activated, but not resting fluorescently
labeled, platelets interact transiently
but robustly with atherosclerotic carotid
arteries of apoE
/
mice in vivo (Huo
et al. 2003). These interactions are main-
ly characterized by transient tethering
and rolling, but firm adhesion is rare
(Huo et al. 2003). Platelet P-selectin is
indispensable during the interactions of
activated platelets with atherosclerotic
arteries (Huo et al. 2003). The endothe-
lial ligand for platelet P-selectin is un-
known. Employing a similar in vivo
model, Massberg et al. (2002) found that
platelet GPIb and GPIIb/IIIa are crucial
for platelet translocation and firm adhe-
sion, respectively. In addition to P-selec-
tin and GPIb, Theilmeier et al. (2002)
classified the VWF as an important mol-
ecule in both resting and activated plate-
let recruitment to atherosclerosis-prone
sites of arteries of rabbits with hypercho-
lesterolemia. These authors (Theilmeier
et al. 2002) also found GPIIb/IIIa-mediat-
ed platelet adhesion. Regarding platelet
adhesion in these studies, the various
methods of endothelial preparation and
definitions of firm adhesion are likely to
influence the results. Consistent with the
observations by Ross (1999), under a
scanning electronic microscope, we did
not find platelets directly adherent to
atherosclerotic endothelium, even after
an injection of in vitro activated platelets.
Because there is no evidence suggesting
that platelets are able to transmigrate,
a substantial platelet accumulation on
luminal surfaces of atherosclerotic arter-
ies should be witnessed if firm platelet
adhesion on the atherosclerotic endothe-
lium occurs. However, we did find plate-
lets associated with monocytes adherent
to the vessel wall.
Platelets interacting with the endothe-
lium may influence the development and
progression of atherosclerosis through a
variety of mechanisms. The platelet
monolayer formed on the injured vessel
provides a platform for leukocyte re-
cruitment to vessel walls. This patho-
logic process—which occurs in the
thrombotic event—may not happen in
the context of spontaneous atherosclero-
sis, because platelets adherent to the
endothelium are, at most, sparse. Our
study (Huo et al. 2003) showed that
platelets transiently interacting with the
atherosclerotic endothelium are able to
deliver and deposit the chemokine
RANTES. This suggests that the contri-
bution of plateletendothelial inter-
actions in atherosclerosis may be to
facilitate the delivery of platelet-derived
proinflammatory factors to atheroscle-
rotic arteries (Figure 1C).
The role of molecules mediating plate-
let endothelial interactions in the devel-
opment of atherosclerosis has been
examined. Platelet P-selectin is indeed
important. Repeated injections of P-selec-
tin-expressing platelets into apoE
/
mice accelerated the formation of athero-
sclerotic lesions (Huo et al. 2003). Recon-
stituted mice whose platelets lack P-
selectin formed smaller lesions than did
control mice (Burger and Wagner 2003).
The effect of VWF on the development of
atherosclerosis is controversial. In pigs
without VWF, inconsistent observations
were reported regarding their resistance
to atherosclerosis (Bowie and Fuster
1980, Nichols et al. 1998). Deficiency of
VWF in a limited number of patients also
did not show any protective role in devel-
opment of atherosclerosis (Sramek et al.
2001). Mice deficient in VWF demonstrat-
ed decreased atherosclerosis (Methia
et al. 2001). Although the effect may be
accredited to the lack of VWF-mediated
platelet interactions, other mechanisms
may also be involved. Endothelial cells
deficient in VWF have a defect in secretion
of P-selectin from their Weibel-Palade
bodies.Thus, endothelial P-selectin-medi-
ated monocyte recruitment in atheroscle-
rosis could be dramatically compromised
in these VWF mutant mice (Denis et al.
2001). Chronic inhibition of GPIb with
blocking antibody protected apoE
/
mice from atherosclerosis (Massberg
TCM Vol. 14, No. 1, 2004 19
et al. 2002). GPIIb/IIIa may be less
relevant to the development of athero-
sclerosis. Patients with Glanzmann
thrombasthenia lacking platelet glyco-
protein a
IIb
h
3
(GPIIb/IIIa) and a
v
h
3
receptors are not protected from athero-
sclerosis (Shpilberg et al. 2002). This is
further demonstrated in h3-deficient
mice. In atherosclerotic mice, deficiency
of h3 even promoted atherosclerosis and
caused significant pulmonary inflamma-
tion (Weng et al. 2003).
Interaction of Activated
Platelets with Leukocytes
P-selectin on activated platelets initiates
their interactions with leukocytes. Among
leukocyte subtypes interacting with acti-
vated platelets, monocytes have a compet-
itive advantage over others in binding
activated platelets (Huo et al. 2003). The
property by which monocytes preferen-
tially bind platelets, a possible basis for
the role of activated platelets in the devel-
opment of atherosclerosis, is unknown.
Engagement of platelets with leukocytes
resultsinactivationoftheleukocyte
integrins Mac-1 and VLA-4. Consequent-
ly, interactions between activated plate-
lets and leukocytes will be stabilized due
to binding of leukocyte integrins to plate-
let intracellular adhesion molecule 2
(ICAM-2) or adhesive plasma proteins
bound to activated GPIIb/IIIa complex.
Recently, it was shown that GPIb is also
a ligand for leukocyte Mac-1 (Simon et al.
2000). The life spans and destinies of
plateletleukocyte aggregates are not
well defined. In a study using primates,
Michelson et al. (2001) found that the life
span of plateletmonocyte aggregates
was not related to platelet P-selectin
shedding. In our in vivo study (Huo et al.
2003), 2 to 3 hours after an injection of
activated platelets, circulating platelet
leukocyte aggregates were no longer de-
tectable and ‘‘normal’’ leukocyte subtype
populations were recovered. This time
course is consistent with the time that
circulating activated platelets take to
shed their P-selectin (Berger et al. 1998),
suggesting that most platelet leukocyte
aggregates end up in disengagement.
However, the possibility that aggregates
sequester into peripheral tissues or mono-
cytes phagocytose platelets bound to their
surfaces cannot be excluded and needs to
be investigated. Alteration in monocyte/
macrophage function resulting from
platelet phagocytosis may systemically
regulate immune and inflammatory reac-
tions (Mulligan et al. 1993).
Platelets binding to monocytes regu-
late monocyte functions. Activated pla-
telets are able to upregulate affinity and/
or avidity of monocyte/leukocyte integ-
rins via P-selectin glycoprotein ligand-1
(PSGL-1) signaling or delivery of plate-
let-derived proinflammatory factors
(Figure 1B). Oxidative burst occurs on
monocytes in response to platelet bind-
ing. These rapid platelet-mediated regu-
lations may play a role in atherosclerosis
by promoting monocyte recruitment
(Figure 1B). Activated platelets are also
able to cause a variety of slow reactions.
Resting monocytes do not express tissue
factor, a protein involved in the initia-
tion of blood coagulation and the forma-
tion of atherosclerotic lesions. However,
upon interaction with platelet P-selectin,
transcription of tissue factor is activated.
Subsequently, tissue factor mRNA, pro-
tein, and activity are induced over sev-
eral hours (Celi et al. 1994), although
this was not confirmed in a later study
(Weyrich et al. 1995). Different cyto-
kines are induced when monocytes bind
platelet P-selectin through PSGL-1 and
are primed by several different synergis-
tic activators. Exposure of monocytes to
platelet P-selectin and platelet activating
factor mobilizes the transcription factor
nuclear factor-nB and induces expres-
sion of tumor necrosis factor a(TNFa)
and monocytes chemotactic protein 1
(MCP-1) (Weyrich et al. 1995). Mono-
cytes exposed to P-selectin and the
platelet-derived chemokine RANTES se-
crete a different set of cytokines, includ-
ing interleukin 8 (IL-8) and MCP-1
(Weyrich et al. 1996). These reactions
significantly contribute to the inflam-
matory and procoagulant response
in vascular thrombotic disease. It is
not clear whether these reactions can
be initiated during transient interac-
tions between monocytes and platelets.
Therefore, the relevance of these reac-
tions in the development of atheroscle-
rosis is unknown.
Platelet-Derived Proinflammatory
Factors in Atherosclerosis
Upon activation, platelets release a
wealth of adhesive and proinflammatory
substances. Main organelles involved in
this release reaction are the open cana-
licular system, the agranules, and the
dense tubular system. Among them, the a
granules are the most important storage
compartments within the platelets for
adhesive proteins and peptides that me-
diate inflammation. Most of the substan-
Figure 1. Mechanisms by which activated platelets participate in the development of
atherosclerosis. (A) No interactions occur between resting platelets and monocytes. (B)
Activated platelets promote monocyte recruitment via platelet monocyte interactions.
Activated platelets interacting with monocytes deliver their proinflammatory factors to
monocytes. Consequently, affinity and/or avidity of monocyte integrins are upregulated and
monocytes arrest on endothelium. Additionally, monocyte – platelet aggregates may employ
platelet P-selectin to mediate aggregates to interact with endothelium. (C) Activated platelets
promote monocyte recruitment via platelet – endo thelial interactions. Activated platelets
transiently interacting with endothelium may deposit their proinflammatory factors on the
surface of endothelium, causing subsequent rolling monocyte arrest. Also, platelet-derived
proinflammatory factors may infiltrate into the vessel wall, triggering vascular cell prolifer-
ation, migration, and inflammation.
20 TCM Vol. 14, No. 1, 2004
ces that are contained within the agran-
ules are synthesized in megakaryocytes,
butitispossiblethatsomeofthem
are endocytosed from the blood plasma.
Several groups of these substances are
relevant to inflammation and atheroscle-
rosis. Platelet factor 4 (PF-4), a member
of the C-X-C subfamily of chemokines, is
derived by limited proteolysis from plate-
let basic protein. PF-4 causes chemotaxis
of monocytes and other leukocytes. Re-
cent studies (Nassar et al. 2003) provide
more evidence for the involvement of PF-
4 in the development of atherosclerosis.
PF-4 enhances the binding of oxidized
low-density lipoprotein (oxLDL) to vas-
cular wall cells, including endothelial
cells and smooth muscle cells. PF-4, co-
localized with oxLDL in atherosclerotic
lesions, especially in macrophage-de-
rived foam cells, is able to dramatically
increase oxLDL esterification by macro-
phages. The presence of glycosaminogly-
cans on the cell surface is required for
these PF-4-mediated reactions (Nassar
et al. 2003, Sachais et al. 2002). RANTES
and macrophage inflammatory protein
(MIP)-1aare members of the C-C chemo-
kine subfamily. RANTES, first purified
as a product of activated T cells, is a
powerful chemoattractant for memory
T lymphocytes and monocytes. MIP-1a
also causes chemotaxis of CD8 T lympho-
cytes, a lymphocyte subset found in ath-
erosclerotic lesions of mice. Platelets
are able to deposit their RANTES on
the luminal surface of atherosclerotic
arteries, suggesting that platelet-derived
chemokines are possibly involved in the
development of atherosclerosis (Huo
et al. 2003, von Hundelshausen et al.
2001). Another a-granule constituent,
platelet-derived growth factor (PDGF),
is a cationic polypeptide composed of two
chains (A and B) that are linked by inter-
chain disulfide bridges. PDGF is the ma-
jor growth factor in platelets stimulating
vascular smooth muscle cell migration
and proliferation associated with intimal
hyperplasia. Also, PDGF is chemotactic
and activates monocytes. Therefore,
PDGF has long been speculated to be
an important participant in the develop-
ment of atherosclerosis. Endothelial
cells lack PDGF receptors and are un-
responsive to PDGF. Therefore, PDGF
may mainly target other vascular cells
in the vessel wall. Macrophages and
foam cells also produce PDGF through-
out the progression of atherosclerosis.
To confirm that PDGF from platelets
contributes to the formation of athero-
sclerotic lesions, direct evidence is need-
ed to show that a portion of PDGF
in atherosclerotic lesions is really ‘‘plate-
let derived.’’
In addition to the above mediators
from platelet agranules, IL-1hand
CD40 ligand (CD40L, CD154) from plate-
lets have recently received intense inter-
est. CD40L—a trimeric, transmembrane
protein of the TNF family originally iden-
tified on activated T cells—has been
found in platelets. CD40L is stored in
the cytoplasm of resting platelets and
rapidly presented on the surface after
activation (Hermann et al. 2001). The
surface-expressed CD40L is subsequently
cleaved over a period of minutes or hours,
generating a soluble but functional frag-
ment, sCD40L. Platelet-derived CD40L is
capable of initiating various inflammato-
ry responses on endothelial cells, includ-
ing production of reactive oxygen species
(Urbich et al. 2002), expression of adhe-
sion molecules (e.g., vascular cell adhe-
sion molecule 1, ICAM-1, and E-selectin),
chemokines (e.g., MCP-1 and IL-8), cyto-
kine IL-6 (Henn et al. 1998), and tissue
factor (Slupsky et al. 1998). In contrast to
CD40L constitutively stored in platelet
cytoplasm, platelet IL-1his synthesized
upon platelet activation (Hawrylowicz
et al. 1989). A portion of IL-1his pre-
sented in its mature form on the platelet
membrane and induces endothelial cell
adhesiveness (Lindemann et al. 2001). It
is possible that these mediators from
the platelet source are involved in the
inflammatory process underlying athero-
sclerosis. Blockade of the CD40/CD40L
pathway has been shown to dramatically
diminish the development of atheroscle-
rosis (Mach et al. 1998). The contribu-
tion of platelet-derived CD40L in this
process has not been evaluated. To
achieve a proinflammatory effect, mem-
brane contact interactions are required
for these factors, especially for IL-1h.
Therefore, studies need to be performed
to investigate whether transient interac-
tions of platelets with endothelium are
able to trigger endothelial inflammation
in the context of atherosclerosis.
Platelet Microparticles
Platelet microparticles, released from ac-
tivated platelets, contain most of the
platelet adhesive molecules and proin-
flammatory factors, and cause a variety
of inflammatory reactions, as do activat-
ed platelets. The role of activated platelets
in the development of atherosclerosis
may be partially attributed to platelet
microparticles.
Conclusion
Thirty years after Ross et al. (1976) pro-
posed the involvement of platelets in
atherosclerosis, direct evidence now sup-
ports the conclusion that activated pla-
telets truly play an important role in the
development of atherosclerosis. Mecha-
nisms regarding the participation of
platelets in atherosclerosis, although par-
tially suggested in primary studies, have
not been fully examined yet. Investiga-
tion of these mechanisms may lead to
new approaches to curb the develop-
ment and progression of atherosclerosis.
Acknowledgments
The authors thank Brian L. Harry and
Matthew C. Hyman for assistance in
preparation of this manuscript. This work
was supported by National Institutes of
Health grant HL-58108 to K.L and AHA
0120404U to Y. Huo.
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PII S1050-1738(03)00169-5 TCM
22 TCM Vol. 14, No. 1, 2004
  • ... Individualmente, las plaquetas están involucradas en la arterioesclerosis, en la activación de citocinas proinflamatorias y, al interaccionar con el endotelio, probablemente también estén relacionadas con la quimiotaxis leucocitaria y con la inflamación en la pared arterial 29,30 . ...
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    Introduction: The platelet-to-lymphocyte (PLR) and neutrophil-to-lymphocyte (NLR) ratios are emerging markers of inflammation. Erythropoietin resistance is associated with increased morbidity and mortality in patients with chronic kidney disease and is influenced by inflammation, among other factors. Therefore, it would be reasonable to expect a relationship between these markers and erythropoietin resistance. Methods: Multicentre cross-sectional study. The records of the haemodialysis sessions of 534 patients belonging to four of our dialysis centres were studied. 137 patients were excluded, so the final number of patients studied was 397. NLR, PLR and the erythropoietin resistance index (ERI) were calculated. Results: The ERI was divided into quartiles and compared with the mean NLR and PLR of the four groups, with these differences being statistically significant (p=0.00058). In the regression analysis, the NLR value was able to predict ERI significantly (p<0.0001) (R2=0.029). The PLR value also predicted ERI significantly (p<0.0001) (R2=0.103). The ability of PLR to predict erythropoietin resistance was measured with the area under the ROC curve (AUC=0.681) (95% CI, 0.541-0.821). A PLR cut-off point of 125.5 would result in a sensitivity of 80.95% and 42.82% specificity. Conclusions: Both PLR and NLR could be considered acceptable markers of erythropoietin resistance. The PLR was a better predictor for the ERI than the NLR.
  • ... Araştırmacılar, aktive trombositlerin lökositlerle özellikle de monositlerle etkileşime girerek lökosit-trombosit agregatları (LTA)'nı oluşturduklarını savunmaktadırlar. 22 Kanser hastalarında yapılan çalışmalarda, LTA değerlerinin C-reaktif protein değeri ile birlikte artış gösterdiği bildirilmiştir. 10 Ayrıca, nötrofiller ile lenfositler arasındaki dengesizliğin tümör hipoksisi ya da nekrozuna sebep olabileceği ve antiapoptotik etkiler ile ilişkili olduğu üzerinde durulmaktadır. ...
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    Objective: The amount of white blood cell (WBC), platelet (PLT) and total ribonucleic acid (RNA) isolated from blood in healthy bitches and bitches with mammary tumors (MT) were compared in this study. Also, determination of the relationship between hematological parameters and clinical findings such as tumor type, mass size, number of mass, age, ulceration and metastasis was aimed. Material and Methods: The material of the research was composed of the data belonging to the 9 healthy bitches approximately 5.95±1.21 years old and 45 bitches with MT approxiamtely 11.19±0.41 years old. Control group included the bithces which were presented to our clinic for ovariohysterectomy. Blood samples were collected in preoperative term for total RNA isolation and hemogram. Total RNA isolation was performed according to kit procedure. Results: Bitches in study and control group were evaluated in terms of age, PLT, WBC and total RNA values. Consequently, age (p<0.001), PLT (p<0.05) and total RNA (p<0.05) values were detected higher in bitches with MT. Also, WBC values were positively correlated with mass size (p<0.05) and total RNA values (p<0.001) in bitches with MT. Additionally, WBC values were higher (p<0.01) in bitches with ulcerated MT. Conclusion: Decrease of PLT values in carcinogenic cases were determined in this study. Also, it was concluded that the amount of total RNA in blood was associated with the amount of WBC in order to detect prognostic tumor markers (biomarkers) in bitches with MT. It is thought that these findings will contribute to molecular studies related to tumor pathophysiology.
  • ... Due to the excessive accumulation of plaque around the arterial wall, blood circulation through these vessels becomes difficult and may eventually lead to the occurrence of cardiovascular disease (Albini et al., 2014). Platelets are thought to play an important role in the pathophysiology of atherosclerosis (Huo and Ley, 2004). Researchers such as Harper AG have found that TRPV1 receptors are present on platelets, which can promote the release of 5-HT and other inflammatory mediators that are beneficial to platelet activation, leading to the formation of atherosclerosis (Harper and Brownlow, 2010). ...
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    Transient receptor potential vanilloid subtype 1 (TRPV1), a member of the transient receptor potential vanilloid (TRPV) channel family, is a nonselective cation channel that is widely expressed in sensory nerve fibers and nonneuronal cells, including certain vascular endothelial cells and smooth muscle cells. The activation of TRPV1 may be involved in the regulation of various physiological functions, such as the release of inflammatory mediators in the body, gastrointestinal motility function, and temperature regulation. In recent years, a large number of studies have revealed that TRPV1 plays an important role in the physiological and pathological conditions of the digestive system, cardiovascular system, and respiratory system, but there is no systematic report on TRPV1. The objective of this review is to explain the function and effects of TRPV1 on specific diseases, such as irritable bowel syndrome, hypertension, and asthma, and to further investigate the intrinsic relationship between the expression and function of TRPV1 in those diseases to find new therapeutic targets for the cure of related diseases.
  • ... Damage to the vascular endothelium triggers the process of atherosclerosis, and activation of platelets by subendothelial matrix-derived molecules such as collagen and fibronectin triggers the adhesion of platelets onto the endothelium. This, in turn, initiates the formation of plaques that harbor immune cells such as monocytes and macrophages which have migrated to the plaque in response to chemotactic signals (159). ...
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    Eph receptors are the largest family of receptor tyrosine kinases and mediate a myriad of essential processes in humans from embryonic development to adult tissue homeostasis through interactions with membrane-bound ephrin ligands. The ubiquitous expression of Eph receptors and ephrin ligands among the cellular players of the immune system underscores the importance of these molecules in orchestrating an optimal immune response. This review provides an overview of the various roles of Eph receptors and ephrin ligands in immune cell development, activation, and migration. We also discuss the role of Eph receptors in disease pathogenesis as well as the implications of Eph receptors as future immunotherapy targets. Given the diverse and critical roles of Eph receptors and ephrin ligands throughout the immune system during both resting and activated states, this review aims to highlight the critical yet underappreciated roles of this family of signaling molecules in the immune system.
  • ... e interaction of endothelial cells (ECs) with platelets is central to pathophysiology of leptin resistance observed in overweight/obesity with a low chronic inflammation that facilitates atherothrombosis in EC matrix [16]. is is the initial step of CVD development. ...
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    This review article stresses the effective role of dietary fish fillet docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on overweight as a risk factor of cardiovascular disease (CVD) via platelet phospholipid modification. Several reports have demonstrated that saturated fat in overweight evokes systemic inflammation and more importantly predisposes it to cardiovascular disorder. Prospective studies have shown that saturated fat is directly proportional to the level of arachidonic acids (AA), precursor of thromboxane in the platelet phospholipid membrane as omega-6 fatty acid in overweight and obese people. Some literature has demonstrated that omega-3 fatty acid from fish fillet ameliorates inflammation, reduces proinflammatory cytokine, inhibits signaling pathway, and regulates the physical composition of inflammatory leukocytes and free radicals (ROS). Yellow stripe scad (YSS) is a local Malaysian fish that has been shown to contain a comparable level of EPA/DHA content as observed in salmon. This review article will focus on the dietary role of fish fillet that will balance the omega-6 fatty acid/omega-3 fatty acid ratio in platelet phospholipid from YSS to manage and prevent healthy overweight/obesity-related risk factor of CVD and to avoid the risk orthodox drug treatment.
  • ... Platelet activity is accepted to play major roles in the development and progression of atherothrombosis, the main cause of CVD [8]. Modulation of platelet activity is largely achieved through prescribed pharmacological agents such as aspirin and glycoprotein inhibitors, approach used in the primary and secondary prevention of coronary events in high risk individuals [9]. ...
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    We examined the ability of tomato pomace extract (by-product) to affect platelet aggregation in healthy humans (clinical pilot study). In phase 1 the tolerance of participants (n = 15; 5 per dose level) ingesting tomato pomace extract across three dose levels (1, 2.5, and 10 g) was evaluated. Phase 2 was a single-blind, placebo-controlled, parallel design human (male, n = 99; 33 per group) pilot intervention trial investigating the acute and repeated dose effects (5 days) of different doses of tomato pomace extract (1 g, 2.5 g or placebo) on platelet aggregation ex vivo. Various flavonoids (coumaric acid, floridzin, floretin, procyanidin B2, luteolin-7-O-glucoside, kaempferol, and quercitin) and nucleosides (adenosine, inosine, and guanosine) were identified in the tomato pomace extract. The clinical study showed that the daily consumption of 1 g of aqueous extract of tomato pomace for 5 days exerted an inhibitory activity on platelet aggregation.
  • ... This interaction mediates platelet aggregation and thrombus formation. Excessive and persistent platelet activation contributes to inflammation and the development of atherothrombosis (176,321,360). Smoking and smoking intensity are strongly associated with increased circulating markers of thrombogenesis, including D-dimer, fibrinogen, and homocysteine (Table 1) (6). ...
    Article
    Although substantial evidence shows that smoking is positively and robustly associated with cardiovascular disease (CVD), the CVD risk associated with the use of new and emerging tobacco products, such as electronic cigarettes, hookah, and heat-not-burn products, remains unclear. This uncertainty stems from lack of knowledge on how the use of these products affects cardiovascular health. Cardiovascular injury associated with the use of new tobacco products could be evaluated by measuring changes in biomarkers of cardiovascular harm that are sensitive to the use of combustible cigarettes. Such cardiovascular injury could be indexed at several levels. Preclinical changes contributing to the pathogenesis of disease could be monitored by measuring changes in systemic inflammation and oxidative stress, organ-specific dysfunctions could be gauged by measuring endothelial function (flow-mediated dilation), platelet aggregation, and arterial stiffness, and organ-specific injury could be evaluated by measuring endothelial microparticles and platelet-leukocyte aggregates. Classical risk factors, such as blood pressure, circulating lipoproteins, and insulin resistance, provide robust estimates of risk, and subclinical disease progression could be followed by measuring coronary artery Ca2+ and carotid intima-media thickness. Given that several of these biomarkers are well-established predictors of major cardiovascular events, the association of these biomarkers with the use of new and emerging tobacco products could be indicative of both individual and population-level CVD risk associated with the use of these products. Differential effects of tobacco products (conventional vs. new and emerging products) on different indexes of cardiovascular injury could also provide insights into mechanisms by which they induce cardiovascular harm.
  • Objective: Patients with psoriasis have impaired vascular health and increased cardiovascular disease (CVD). Platelets are key players in the pathogenesis of vascular dysfunction in cardiovascular disease and represent therapeutic targets in cardiovascular prevention. The object of this study was to define the platelet phenotype and effector cell properties on vascular health in psoriasis and evaluate whether aspirin modulates the platelet-induced phenotype. Approach and Results: Platelets from psoriasis patients (n=45) exhibited increased platelet activation (relative to age- and gender-matched controls, n=18), which correlated with psoriasis skin severity. Isolated platelets from psoriasis patients demonstrated a 2- to 3-fold (P<0.01) increased adhesion to human aortic endothelial cells and induced proinflammatory transcriptional changes, including upregulation of IL 8 (interleukin 8), IL1β, and COX-2 (cyclooxygenase-2). Platelet RNA sequencing revealed an interferon signature and elevated expression of COX-1, which correlated with psoriasis disease severity (r=0.83, P=0.01). In a randomized trial of patients with psoriasis, 2 weeks of 81 mg low-dose aspirin, a COX-1 inhibitor, reduced serum thromboxane (Tx) B2 and reduced brachial vein endothelial proinflammatory transcript expression >70% compared with the no-treatment group (P<0.01). Improvement in brachial vein endothelial cell inflammation significantly correlated with change in serum TxB2 (r=0.48, P=0.02). Conclusions: In patients with psoriasis, platelets are activated and induce endothelial cell inflammation. Low-dose aspirin improved endothelial cell health in psoriasis via platelet COX-1 inhibition. These data demonstrate a previously unappreciated role of platelets in psoriasis and endothelial cell inflammation, which suggests that aspirin may be effective in improving vascular health in patients with psoriasis. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03228017.
  • Article
    Full-text available
    Inflammation is ubiquitous in the body, triggering desirable immune response to defend against dangerous signals or instigating undesirable damage to cells and tissues to cause disease. Nanomedicine holds exciting potential in modulating inflammation. In particular, cell membranes derived from cells involved in the inflammatory process may be used to coat nanotherapeutics for effective targeted delivery to inflammatory tissues. Herein, the recent progress of rationally engineering cell membrane‐based nanotherapeutics for inflammation therapy is highlighted, and the challenges and opportunities presented in realizing the full potential of cell‐membrane coating in targeting and manipulating the inflammatory microenvironment are discussed. Recent advances of rationally engineering cell membrane‐based nanotherapeutics for inflammation therapy are summarized and the state‐of‐the‐art cell membrane engineering, extraction, and cloaking technologies are introduced. The challenges and opportunities of such bioinspired nanomedicine allow for the realization of the full potential of cell‐membrane coating in targeting and manipulating the inflammatory microenvironment.
  • Article
    Objectives: Platelet/lymphocyte ratio is considered to be a recent biomarker which is not only related with inflammation but also associated with the atherosclerotic process. In this study, we aimed to investigate the relationship between carotid artery stenosis, platelet/lymphocyte ratio, neutrophil/lymphocyte ratio, and mean platelet volume in patients undergoing carotid endarterectomy. Methods: A total of 160 patients (127 males, 33 females; mean age 69.98 ± 9.76 years; range 48-92 years), who were undergoing carotid endarterectomy due to severe carotid artery stenosis, were evaluated and compared with 201 patients (140 males, 61 females, mean age 66.30 ± 9.24 years, range 41-90 years) without severe carotid artery stenosis. The patients were divided into four groups with respect to the carotid artery stenosis as: Group I (<50% stenosis), Group II (50-70% stenosis), Group III (70-90% stenosis), and Group IV (90-99% stenosis). Results: Platelet/lymphocyte ratio, neutrophil/lymphocyte ratio and mean platelet volume were found higher in Group IV (patients with severe carotid artery stenosis) (p < 0.01) and were positively correlated with the degree of stenosis (p < 0.01). Platelet/lymphocyte ratio is an independent predictor for post operative stroke (p = 0.047) at multivariate analysis. A threshold level of 145.304 of platelet/lymphocyte ratio combined with a sensitivity 83.3% and specificity 73.8% (95% CI, 0.802-0.921, area under the curve = 0.862 ± 0.03; p = 0.002) for the identification of post operative stroke. Conclusions: This retrospective study suggests that platelet/lymphocyte ratio in the blood which was taken preoperatively could be considered as an additional, easy, and inexpensive method to predict a possible higher incidence of postoperative stroke after carotid endarterectomy.
Literature Review
  • Article
    The influence of platelets on the cellular metabolism of atherogenic lipoproteins has not been characterized in detail. Therefore, we investigated the effect of platelet factor 4 (PF4), a cationic protein released in high concentration by activated platelets, on the uptake and degradation of low-density lipoprotein (LDL) via the LDL receptor (LDL-R). LDL-R–dependent binding, internalization, and degradation of LDL by cultured cells were inhibited 50%, 80%, and 80%, respectively, on addition of PF4. PF4 bound specifically to the ligand-binding domain of recombinant soluble LDL-R (half-maximal binding 0.5 μg/mL PF4) and partially (approximately 50%) inhibited the binding of LDL. Inhibition of internalization and degradation by PF4 required the presence of cell-associated proteoglycans, primarily those rich in chondroitin sulfate. PF4 variants with impaired heparin binding lacked the capacity to inhibit LDL. PF4, soluble LDL-R, and LDL formed ternary complexes with cell-surface proteoglycans. PF4 induced the retention of LDL/LDL-R complexes on the surface of human fibroblasts in multimolecular clusters unassociated with coated pits, as assessed by immuno-electron microscopy. These studies demonstrate that PF4 inhibits the catabolism of LDL in vitro in part by competing for binding to LDL-R, by promoting interactions with cell-associated chondroitin sulfate proteoglycans, and by disrupting the normal endocytic trafficking of LDL/LDL-R complexes. Retention of LDL on cell surfaces may facilitate proatherogenic modifications and support an expanded role for platelets in the pathogenesis of atherosclerosis.
  • Article
    The advanced lesions of atherosclerosis represent the culmination of a specialized form of chronic inflammation followed by a fibroproliferative process that takes place within the intima of the affected artery. Proliferation of smooth muscle cells and generation of connective tissue occur. Proliferation results from interactions between arterial smooth muscle, monocyte-derived macrophages, T lymphocytes, and endothelium. The initial lesion of atherosclerosis, the fatty streak, begins as an accumulation of monocytederived macrophages and T lymphocytes, which adhere and migrate into the intima of the affected artery. Smooth muscle cells, which are present in the intima or which migrate into the intima from the media, then replicate. Monocyte-derived macrophages and T cells also replicate during lesion formation and progression due to the production of cytokines and growth-regulatory molecules. These molecules determine whether there is proliferation and lesion progression or inhibition of proliferation and lesion regression. Several growthregulatory molecules may play critical roles in this process, including platelet-derived growth factor (PGDF), transforming growth factor beta, fibroblast growth factor, heparinbinding epidermal growth factor-like growth factor, and others. PDGF may be one of the principal components in this process because protein containing the PDGF B-chain has been demonstrated within activated lesion macrophages during every phase of atherogenesis. The presence of this growth factor and its receptors on lesion smooth muscle cells creates opportunities for smooth muscle chemotaxis and replication. Smooth muscle proliferation depends upon a series of complex signals based upon cellular interactions in the local microenvironment of the artery. The intracellular signalling pathways for mitogenesis versus chemotaxis are being investigated for smooth muscle. The roles of the cytokines and growth-regulatory peptides involved in these cellular interactions represent critical points of departure for intervention and the development of new diagnostic methods. In addition, magnetic resonance imaging has been developed to demonstrate the fine structure of lesions of atherosclerosis in peripheral arteries not subject to cardiac motion. This noninvasive methodology holds great promise for the future of these approaches.
  • Article
    Background: Circulating platelets and chemoattractant proteins, such as the CC chemokine RANTES, contribute to the activation and interaction of monocytes and endothelium and may thereby play a pivotal role in the pathogenesis of inflammatory and atherosclerotic disease. Methods and results: The binding of RANTES to human endothelial cells was detected by ELISA or immunofluorescence after perfusion with platelets or exposure to their supernatants. Monocyte arrest on endothelial monolayers or surface-adherent platelets was studied with a parallel-wall flow chamber and video microscopy. We show that RANTES secreted by thrombin-stimulated platelets is immobilized on the surface of inflamed microvascular or aortic endothelium and triggers shear-resistant monocyte arrest under flow conditions, as shown by inhibition with the RANTES receptor antagonist Met-RANTES or a blocking RANTES antibody. Deposition of RANTES and its effects requires endothelial activation, eg, by interleukin-1beta, and is not supported by venous endothelium or adherent platelets. Immunohistochemistry revealed that RANTES is present on the luminal surface of carotid arteries of apolipoprotein E-deficient mice with early atherosclerotic lesions after wire-induced injury or cytokine exposure. In a mechanistic model of atherogenesis, monocyte adherence on endothelium covering such lesions was studied in murine carotid arteries perfused ex vivo, showing that the accumulation of monocytic cells in these carotid arteries involved RANTES receptors. Conclusions: The deposition of RANTES by platelets triggers shear-resistant monocyte arrest on inflamed or atherosclerotic endothelium. Delivery of RANTES by platelets may epitomize a novel principle relevant to inflammatory or atherogenic monocyte recruitment from the circulation.
  • Article
    The aortas of 11 pigs (aged 1-3 yr) with homozygous von Willebrand's disease (vWd) were compared with those of 11 normal pigs of the same ages. Six of the controls exhibited multiple arteriosclerotic plaques with intimal thickening of 63-130 mum. In contrast, none of the pigs with vWd had multiple plaques, and only one had a lesion >2 mm in diameter. In a subsequent study, 3-mo-old pigs (11 controls and 7 with homozygous vWd) were placed on a 2% cholesterol diet for up to 6 mo. All of the controls developed arteriosclerotic plaques in the aorta, and in nine of the controls, at least 13% of the entire surface was involved. Intimal thickness ranged up to 390 mum. In contrast, four of the pigs with vWd did not develop such lesions, two developed arteriosclerotic lesions affecting 6 and 7% of the aortic surface, and the seventh had 13% of the aortic surface involved. Most of the pigs with vWd, however, developed flat fatty lesions in contrast to the normal pigs whether on the normal or the high cholesterol diet. There was blue staining of the flat fatty lesions when two pigs with vWd were injected with Evans blue dye antemortem. By electron microscopy, severe endothelial damage was apparent, but there was no intimal proliferation. The coincidence of the impaired platelet-arterial wall interaction and lack of arteriosclerosis in this bleeding disease is discussed.
  • Article
    In this review, the importance of smooth muscle cell proliferation as a key event in atherogenesis is emphasized. To convey a better understanding of the factors which can influence smooth muscle cell proliferation, some current information about arterial cell biology was summarized first. Clearly, knowledge concerning the normal characteristics of arterial endothelial and smooth muscle cells must form the basis for any hypothesis concerning the proliferation of smooth muscle cells observed in atherosclerosis. The recognition that smooth muscle proliferation is a sine qua non of atherogenesis is relatively recent. Our ability to focus on this process has been heightened by the development of the 3 hypotheses discussed: the response to injury hypothesis, the monoclonal hypothesis and the clonal selection hypothesis. It should be apparent that the 3 hypotheses are not necessarily mutually exclusive; in fact, in some interesting ways, they are complementary. Each focuses on different aspects of smooth muscle proliferation, and each raises questions that must be seriously considered to better understand the cause and pathogenesis of atherosclerosis. The phenomenon of arterial smooth muscle cell proliferation undoubtedly has much in common with cell proliferation in other tissues. Therefore, fundamental research concerning factors that control cell proliferation will be essential to an understanding of atherogenesis. In addition, research concerning endothelial injury and the response of thrombocytes and arterial cells to this injury will be important, irrespective of what particular hypothesis is proposed. In conclusion, atherosclerosis is a broad category of disease thay may affect different parts of the arterial system in different ways. It may result from endothelial 'injury', which may have different manifestations in different sites in different arteries, but which produces common alterations in the endothelium and the smooth muscle which result in the proliferative smooth muscle response, increased connective tissue formation and lipid deposition that we call atherosclerosis. (131 references)
  • Article
    Diabetes is accompanied by impaired platelet function and accelerated vascular disease. To find out whether a correlation exists between these two complications, and if modifications occurring in diabetic platelets influence their relationship with endothelium, we have studied the interaction between platelets isolated from plasma of diabetic patients and bovine valvular endothelial cells (VEC), in culture. For quantitative analysis, normal and diabetic [3H]-adenine-labeled platelets were incubated with confluent VEC grown in Dulbecco's modified Eagle medium, containing 4.5 g/l glucose, for 30 min at 37 degrees C. After extensive washing and solubilization of the monolayer, the calculated adhesion index showed a two-fold increased adherence of diabetic platelets to VEC as compared to normal platelets. Statistical analysis (by Pitman randomization test) indicated that the adhesion was significantly higher (p = 0.0003) than that of normal platelets to VEC. To partially identify the membrane components implicated in the adhesion process, either platelets or VEC were treated with neuraminidase, trypsin or heparinase prior to the adhesion assay. Trypsin or neuraminidase treatment of platelets significantly diminished their adherence to VEC, suggesting a role of platelets sialylated glycoproteins in the adhesion process. Neuraminidase or heparinase treatment of VEC increased the adhesion of both normal and diabetic platelets, indicating that the cell membrane sialyl residues and heparan sulfate participate in the normal thromboresistant properties of VEC. Transmission and scanning electron microscopy revealed a close apposition between platelets and VEC with the formation of an adhesion plaque, characterized by fine fibrillar bridges between the plasma membranes of the two cells.(ABSTRACT TRUNCATED AT 250 WORDS)