Adiponectin and Hypertension

Abstract

Adipose tissue secretes a variety of bioactive molecules, also known as adipocytokines or adipokines. Obesity, in particular, visceral fat accumulation, is implicated in the dysregulated secretion of adipocytokines, which can contribute to the development of metabolic syndrome and cardiovascular diseases. Adiponectin is an adipocytokine that is exclusively secreted from adipose tissue, but its plasma levels are reduced in obese subjects, especially those with visceral fat accumulation. Adiponectin has a variety of protective properties against obesity-linked complications, such as hypertension, metabolic dysfunction, atherosclerosis, and ischemic heart disease. Adiponectin exerts the beneficial effects on vascular disorders by directly affecting components of vascular tissue. This review will discuss clinical and experimental findings that examine the role of adiponectin in regulation of hypertension and vascular function.
American Journal of Hypertension advance online publication 7 October 2010;. doi:10.1038/ajh.2010.216

Full text

AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUM BER 3 | 263269 | MARCH 2011 263
STATE OF THE ART
nature publishing group
Obesity, in particular, visceral fat accumulation, causes a
cluster of hypertension, type 2 diabetes, and dyslipidemia, also
referred to as metabolic syndrome. e accumulated disor-
ders induced by visceral fat accumulation lead to cardiovascu-
lar disease, which is one of the leading causes of mortality in
western countries. Adipose tissue produces and secretes many
bioactive molecules,1–5 which are known as adipocytokines
or adipokines.3,6 Dysregulated production of adipocytokines,
such as tumor necrosis factor-α (TNF-α), leptin, and plasmino-
gen activator inhibitor type 1, is associated with the pathogen-
esis of metabolic syndrome and cardiovascular diseases.1–5
Adiponectin is almost exclusively expressed in adipose
tissue7,8 and exists abundantly at the range 3–30 µg/ml in
plasma. Interestingly, plasma adiponectin levels are decreased
in obese patients, particularly those with excess visceral fat,
and its plasma levels are inversely correlated with visceral
adiposity.9,10 Low concentration of adiponectin, so-called
hypoadiponectinemia, is closely associated with obesity-
related diseases including hypertension, type 2 diabetes, and
cardiovascular disease.11–14 Numerous experimental studies
have shown that adiponectin displays a variety of protective
actions on obesity-induced pathological conditions, including
hypertension, insulin resistance, hepatic steatosis, atheroscle-
rosis, and ischemic heart disease.15–19 Furthermore, adiponec-
tin exerts antiatherogenic and anti-inammatory eects by its
ability to act on vascular component cells including endothe-
lial cells and macrophages.20–26 In this review, we will focus on
the key role of adiponectin in regulating vascular homeostasis.
ADIPONECTIN AS A BIOMARKER FOR HYPERTENSION
A number of clinical studies have demonstrated the rela-
tionship of plasma adiponectin concentration with
hypertension.11,12,27,28 Adamczak et al. showed for the rst
time that plasma adiponectin levels are signicantly lower
in patients with essential hypertension compared with those
in body mass index-matched normotensive subjects.11 An
inverse correlation is observed between adiponectin con-
centration and mean systolic and diastolic blood pressure.
Similarly, adipo nectin levels are negatively associated with
blood pressure in patients with type 2 diabetes and metabolic
syndrome.29 In addition, Iwashima et al. have demonstrated
that a hypoadiponectinemia is a risk factor for hypertension
independent of insulin resistance and diabetes.12
Adiponectin has been reported to associate with the pro-
gression of hypertension. Chow et al. for the rst time demon-
strated an inverse relation between plasma adiponectin
concentration and the future development of hypertension by
prospective analysis of Chinese subjects for 5 years.30 In this
study, 70 normotensive, nondiabetic subjects, who developed
hypertension by the end point, were compared with 140 age-
and sex-matched subjects who were normotensive during the
observed periods. Hypoadiponectinemia at baseline is a strong
predictor of future hypertension even aer adjusting the con-
founding factors such as mean blood pressure, C-reactive
protein, body mass index, and waist circumference. Subjects
with hypoadiponectinemia show three times higher morbidity
of future hypertension than those with normal range of
adiponectin levels.
Analysis of mutations in human adiponectin gene provides
further information about the link between adiponectin and
hypertension. Among several single-nucleotide polymor-
phisms of adiponectin gene, single-nucleotide polymorphism
at position 164 (TC genotype of the I164T) has been associated
Adiponectin and Hypertension
Koji Ohashi1, Noriyuki Ouchi1 and Yuji Matsuzawa2
1Department of Molecular Cardiology, Nagoya University Graduate School
of Medicine, Nagoya, Japan; 2Sumitomo Hospital, Emeritus Osaka University,
Osaka, Japan. Correspondence: Noriyuki Ouchi (nouchi@med.nagoya-u.ac.jp)
Received 12 August 2010; first decision 3 September 2010; accepted
3 September 2010.
© 2011 American Journal of Hypertension, Ltd.
Adipose tissue secretes a variety of bioactive molecules, also known
as adipocytokines or adipokines. Obesity, in particular, visceral
fat accumulation, is implicated in the dysregulated secretion of
adipocytokines, which can contribute to the development of
metabolic syndrome and cardiovascular diseases. Adiponectin is
an adipocytokine that is exclusively secreted from adipose tissue,
but its plasma levels are reduced in obese subjects, especially
those with visceral fat accumulation. Adiponectin has a variety of
protective properties against obesity-linked complications, such as
hypertension, metabolic dysfunction, atherosclerosis, and ischemic
heart disease. Adiponectin exerts the beneficial effects on vascular
disorders by directly affecting components of vascular tissue. This
review will discuss clinical and experimental findings that examine
the role of adiponectin in regulation of hypertension and vascular
function.
Keywords: adiponectin; blood pressure; endothelial cell; hypertension;
macrophage; metabolic syndrome
American Journal of Hypertension, advance online publication 7 October 2010;
doi:10.1038/ajh.2010.216

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264 MARCH 2011 | VOLUME 24 NUMBER 3 | AMERICAN JOURNAL OF HYPERTENSION
with hypoadiponectinemia and high blood pressure in Japanese
population.12 I164T mutation is also related to metabolic syn-
drome and coronary heart disease.31,32 Hypoadiponectinemia
caused by I164T mutation is due, at least in part, to disturbance
of secretion of adiponectin into plasma.33
An experimental study also supports the notion that adipo-
nectin modulates blood pressure. Adiponectin-knockout
mice show no phenotype of hypertension under unstressed
conditions. However, aer high-salt diet feeding, adiponectin-
knockout mice exhibit signicantly higher levels of systolic
blood pressure compared with wild-type (WT) mice inde-
pendent of insulin resistance.15 Adiponectin replenishment
by adenovirus system ameliorates the high-salt diet-induced
hypertension of adiponectin-knockout mice. Adenovirus-
mediated overexpression of adiponectin dramatically reduces
the systolic blood pressure in a genetic mouse model of
obesity and hypertension. Furthermore, in aldosterone infu-
sion model with uninephrectomy, adiponectin-knockout
mice develop higher systolic blood pressure compared with
WT mice.34 Aldosterone-infused adiponectin-knockout
mice also show severer le ventricular hypertrophy and pul-
monary congestion compared with control mice. Analysis
of diastolic heart function by echocardiogram revealed that
adiponectin-knockout mice have severe diastolic dysfunc-
tion following aldosterone infusion.34 us, adiponectin-
deciency contributes to the development of hypertension
under conditions of stress.
Collectively, hypoadiponectinemia induced by visceral fat
accumulation is highly associated with hypertension.
ADIPONECTIN AND ENDOTHELIAL FUNCTION
Endothelial dysfunction is an important feature predispos-
ing to vascular disease and is closely associated with obesity-
linked complications including hypertension and insulin
resistance.35 Numerous studies have shown that adiponectin
is benecial for endothelial function. Plasma adiponectin level
is closely correlated with the vasodilator response to reactive
hyperemia in hypertensive patients.36 Likewise, plasma adipo-
nectin level is positively associated with the forearm blood
ow response during reactive hyperemia in apparently healthy
men.37 Furthermore, hypoadiponectinemia has been reported
to associate with impaired endothelium-dependent vasodila-
tion of the brachial artery in diabetic patients.38 In support of
these clinical data, adiponectin-knockout mice display impair-
ment of endothelium-dependent vasodilation in response to
acetylcholine compared with control mice when fed an athero-
genic diet.36
Endothelial nitric oxide synthase (eNOS) and nitric oxide
(NO) are crucial regulators of vascular homeostasis, in parti-
cular, endothelial function.39,40 Accumulating evidence indi-
cates that adiponectin functions as an endogenous modulator
of endothelial-derived NO production. Adiponectin-knockout
mice have lower levels of eNOS transcripts in aorta and NO
metabolites in plasma as well as higher blood pressure com-
pared with WT mice aer high-salt diet feeding.15 Systemic
administration of adiponectin to high salt-fed adiponectin-
knockout mice lowers the elevated blood pressure and restores
the reduced eNOS transcripts in aorta. Of importance, inhi-
bition of NOS reverses the reduction of blood pressure
caused by adiponectin in adiponectin-knockout mice. us,
adiponectin-deciency participates in salt-sensitive hyperten-
sion through modulation of eNOS function.
Nishimura et al. have shown that adiponectin-knockout
mice develop exacerbated cerebral ischemia-reperfusion
injury with reduced eNOS activation in ischemic brain tissue
and decreased NO metabolites in plasma compared with WT
mice.41 Kondo et al. reported that caloric restriction promotes
revascularization in response to tissue ischemia through an
adiponectin-mediated activation of eNOS.42 In another article,
adiponectin-knockout mice exhibit reduced levels of endothe-
lial NO in the vessel walls.43 ese ndings strongly suggest
that the favorable actions of adiponectin on vascular response
are mediated, at least in part, by its ability to activate eNOS.
A number of in vitro experiments reveal the important role
of adiponectin in regulating eNOS activity and NO production.
Adiponectin stimulates phosphorylation of eNOS at Ser-1177
in human endothelial cells through its ability to activate AMP-
activated protein kinase signaling.20 Adiponectin also stimu-
lates NO production in vascular endothelial cells through
phosphorylation of eNOS22 (Figure 1). e stimulatory eects
Adiponectin
CRT/CD91
COX-2
Endothelial cell function
Akt
AdipoR1/R2
AMPK
eNOS
PGI2NO
Figure 1 | Protective actions of adiponectin on endothelial cell function.
Adiponectin ameliorates endothelial cell function through two independent
regulatory mechanisms within endothelial cells. Adiponectin enhances
eNOS activity and subsequent NO production through Adipo R1/R2-AMPK
signaling. Adiponectin stimulates cyclooxygenase-2 (COX-2) expression
and prostaglandin I2 (PGI2) production through calreticulin (CRT)/CD91-
dependent Akt signaling pathway. AMPK, AMP-activated protein kinase;
eNOS, endothelial nitric oxide synthase; NO, nitric oxide.

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AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUM BER 3 | MARCH 2011 265
of adiponectin on eNOS activity and NO production are
shown to be mediated through adiponectin receptors, Adipo
R1/R2 and their intracellular adaptor molecule APPL1.44 In
addition, treatment of bovine endothelial cells with globular
fragment of adiponectin increases eNOS mRNA and protein
expressions, leading to increased production of NO.45 us,
these results suggest that hypoadiponectinemia can cause
decreased endothelium-derived NO production and subse-
quent endothelial dysfunction, ultimately contributing to the
development of hypertension.
In addition to the above-mentioned signaling pathway, adi-
ponectin promotes endothelial cell function through another
mechanism. Endothelial cyclooxygenese-2 (COX-2) and its
metabolites play an important role in control of vascular func-
tions such as vascular tone and endothelial function.46–49
A recent report with mouse genetic experiments shows that
adiponectin promotes revascularization in response to tissue
ischemia through COX-2-dependent mechanism.24 Deletion of
COX-2 in an endothelial specic manner results in suppression
of adiponectin-induced revascularization response in ischemic
muscle. In cultured endothelial cells, recombinant adiponectin
treatment signicantly increases COX-2 expression and pro-
motes endothelial cell function via activation of Akt-dependent
COX-2 signaling pathway. Importantly, adiponectin-mediated
endothelial cell protection via Akt-COX-2 regulatory axis is
largely dependent on the ability of adiponectin to associate with
a newly recognized adiponectin-binding protein, calreticulin/
its adaptor protein CD91 on the surface of endothelial cells
(Figure 1). Consistent with these ndings, adiponectin pro-
motes a clearance of apoptotic body by macrophages through
a calreticulin/CD91-dependent pathway.50 Furthermore, adi-
ponectin-knockout mice display reduced levels of prostaglan-
din I synthase mRNA in aorta and circulating prostaglandin
I2 metabolite following high salt feeding.15 Adiponectin sup-
plementation using adenovirus system restores the reduced
levels of prostaglandin I synthase transcript in aorta and pros-
taglandin I2 metabolite in plasma in high salt-fed adiponectin-
knockout mice. ese observations indicate that adiponectin
improves endothelial cell function, at least in part, through
COX-2-prostaglandin I2-dependent pathway (Figure 1).
Taken together, adiponectin protects against endothe-
lial dysfunction via at least two regulatory pathways involv-
ing AMP-activated protein kinase-eNOS signaling and
COX-2-prostaglandin I2 signaling within endothelial cells.
Future researches with mouse genetic models are needed to
dissect the receptor-mediated signaling pathways involved in
the vascular protection by adiponectin.
ADIPONECTIN AND MACROPHAGE FUNCTION
A number of epidemiological studies have indicated that
plasma adiponectin concentration is negatively correlated
with the inammatory markers C-reactive protein and the
proinammatory cytokine interleukin-6 in blood stream.51–54
ese observations are in agreement with the experimental
data showing the protective properties of adiponectin against
inammation. Adiponectin has been reported to aect the
function and phenotype of macrophages by multiple mecha-
nisms, thereby displaying various anti-inammatory actions.
Adiponectin attenuates agonist-stimulated production of a
proinammatory cytokine TNF-α in cultured macrophages,
which is accompanied by diminished nuclear factor-κB
activation.55,56 Because TNF-α acts as a key modulator that
associates with the pathology of obesity-linked metabolic and
vascular disorders, the salutary actions of adiponectin on vari-
ous pathological processes may be mediated partly through
suppression of TNF-α production in macrophages. In line with
this notion, a recent report showed that adiponectin protects
against ischemia-induced vascular injury in retina via modu-
lation of TNF-α inammatory response.57
One of the crucial steps in atherogenesis is adherence of
monocytes to damaged endothelial cells and subsequent
monocyte-to-macrophage transformation. Adiponectin sup-
presses adherence of monocytes to TNF-α-stimulated endothe-
lial cells by inhibiting expression of adhesion molecules.4,14
Adiponectin also suppresses expression of class A scavenger
receptor in human macrophages and prevents transforma-
tion of macrophages to foam cells.58 Consistent with these
in vitro ndings, overexpression of adiponectin protects
against the development of atherosclerosis in a mouse model
of atherosclerosis.18,59 Furthermore, adiponectin promotes the
ecient removal of apoptotic debris from the body by mac-
rophages through a cell surface calreticulin/CD91 system on
macrophage, thereby preventing inammation and immune
system dysfunction.50
Recent evidence suggests that adipose tissue macro-
phages play an important role in the chronic inammatory
state and metabolic dysfunction associated with obesity.60,61
Interestingly, macrophages from fat tissue of lean sub-
jects express markers of the M2 or “alternatively activated”
macrophage, whereas obesity leads to a reduction of M2
markers and an increase of genes associated with the M1 or
“ classically activated” macrophage62 (Figure 2). M1 macro-
phage polarization causes inammation and tissue destruc-
tion, whereas the M2 macrophage is believed to display an
anti-inammatory phenotype and rather confer wound repair
and vascular protection (Figure 2).
A recent study has shown that peritoneal macrophages and
stromal vascular fractions (SVF), which include macrophages
and vascular components except for adipocytes, isolated from
adiponectin-knockout mice display an activated M1 pheno-
type.25 Conversely, adenovirus-mediated systemic delivery of
adiponectin promotes expression of arginase-1, a well-known

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266 MARCH 2011 | VOLUME 24 NUMBER 3 | AMERICAN JOURNAL OF HYPERTENSION
M2 marker, in peritoneal macrophages and SVF in WT and
adiponectin-knockout mice. In vitro cultured experiments also
show that treatment of mouse peritoneal macrophages and
SVF with recombinant adiponectin protein leads to upregula-
tion of M2 markers including arginase-1, macrophage galac-
tose N-acetyl-galactosamine specic lectin-1 (Mgl-1) and
interleukin-10. In contrast, treatment with adiponectin protein
attenuates expression of M1 markers including TNF-α, inter-
leukin-6, and monocyte chemotactic protein-1 in cultured
mouse macrophage and SVF. e elevation of M2 markers and
suppression of M1 markers following adiponectin treatment
are also found in cultured human monocyte-derived macro-
phages and SVF (Figure 2). erefore, it is conceivable that
adiponectin ameliorates vascular disorders including endothe-
lial dysfunction by its ability to promote macrophage polari-
zation toward the anti-inammatory phenotype. However, the
molecular mechanism by which adiponectin regulates macro-
phage behavior has not been fully understood. Future studies
are necessary to elucidate the adiponectin signaling pathways
that are involved in changes in macrophage function and
phenotype.
ADIPONECTIN AND RENINANGIOTENSIN SYSTEM RAS
e RAS plays a crucial role in cardiovascular homeo stasis
by regulating blood pressure and vascular function.63,64
Accumulating evidence indicates the important role of RAS in
regulation of adiponectin production. Watanabe et al. showed
that an antihypertensive drug angiotensin II type 1 receptor
blocker (ARB) losartan treatment for 3 months increases
plasma adiponectin concentration in patients with essential
hypertension. In contrast, treatment with a calcium blocker,
amlodipine, has no eect on adiponectin levels in this popu-
lation.65 Similarly, losartan treatment for 6 months increases
serum adiponectin levels in hypertensive patients with meta-
bolic syndrome.66 Furthermore, plasma adiponectin levels are
signicantly increased aer 8 weeks of treatment with an ARB
telmisartan in patients with essential hypertension.67 It has
also been shown that both telmisartan and another ARB irbe-
sartan increase circulating adiponectin levels in patients with
insulin resistance and hypertension.68 erefore, inhibition of
angiotensin II type 1 receptor-mediated signaling appears to
lead to elevation of adiponectin levels in hypertensive subjects.
Conversely, administration of angiotensin II to rats fed with
a high-fructose diet signicantly decreases plasma adipo nectin
levels.69 Interestingly, plasma adiponectin concentration
decreases before the blood pressure increase aer angiotensin
II infusion. Angiotensin II is known to stimulate generation
of reactive oxygen species. Furukawa et al. demonstrated that
the increased reactive oxygen species cause dysregulation of
adipocytokines including reduced levels of adiponectin and
that hydrogen peroxide, one of reactive oxygen species, inhib-
its adiponectin expression in adipose tissue.70 us, activa-
tion of RAS reduces adiponectin production partly through
enhancement of reactive oxygen species generation. To sup-
port this hypothesis, another ARB olmesartan has been shown
to restore decreased level of adiponectin in obese animals,
which is accompanied by decrease in oxidative stress in adi-
pose tissue.71
Benson et al. have shown that telmisartan functions to pro-
mote peroxisome proliferator-activated receptor-γ (PPAR-γ)
activity as a partial agonist for PPAR-γ.72 Treatment of 3T3-L1
adipocytes with telmisartan results in upregulation of aP2 and
CD36, which are target molecules of PPAR-γ. e administra-
tion of PPAR-γ ligands, thiazolidinediones, has been reported
to robustly increase the plasma adiponectin concentrations
in human and mouse studies.73 iazolidinedione treatment
has been shown to enhance expression and secretion of adipo-
nectin in cultured adipocytes.73–77 erefore, PPAR-γ acti-
vation by ARBs could be another mechanism of adiponectin
upregulation by these agents.78
Several clinical studies have demonstrated that, in addition
to blood pressure-lowering eects, ARBs have various bene-
cial actions including improvement of glucose and lipid metab-
olism and vascular function. In a double-blinded randomized
trial in patients with essential hypertension, losartan-treated
groups exhibit signicantly lower new-onset diabetes and
stroke compared to atenolol during mean 4.8-year follow-up
Endothelial cell
Adiponectin
Macrophage
M2 M1
NO
PGI2
Arginase-1 TNF-α
MCP-1
IL-6
IL-10
Anti-inflammatory Proinflammatory Endothelial function
Mgl-1
Vascular protection
Figure 2 | Potential mechanism of vascular protection by adiponectin.
Adiponectin attenuates the phenotype of M1 macrophages, which display
upregulation of proinflammatory cytokines including tumor necrosis factor-α
(TNF-α), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1).
Adiponectin promotes the phenotype of M2 macrophages, which show
upregulation of arginase-1 (Arg-1), interleukin-10 (IL-10), and macrophage
galactose N-acetyl-galactosamine specific lectin-1 (Mgl-1). Adiponectin
ameliorates endothelial cell function via increase in NO and PGI2 production
in endothelial cells. It is plausible that adiponectin exerts protective actions
on vascular function through its ability to improve function of macrophage
and endothelial cell. NO, nitric oxide; PGI2, prostaglandin I2.

Adiponectin and Hypertension
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AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUM BER 3 | MARCH 2011 267
time.79 Valsaltan, another ARB, also reduces new-onset type 2
diabetes in nondiabetic hypertensive patients compared with
amlodipine.80,81 Telmisartan treatment decreases total and
low-density lipoprotein cholesterol levels and hemoglobin
A1c in patients with essential hypertension.82 In addition,
telmisartan improves the pulse-wave velocity accompanying
with a decreased levels of asymmetric dimethylarginine, an
endogenous eNOS inhibitor produced by vascular endothe-
lial cells.82 Considering the protective actions of adiponectin
on metabolic syndrome, multiple functions by ARBs could be
attributed to induction of adiponectin.
Collectively, these ndings suggest that adiponectin upregu-
lation by RAS inhibition is benecial for not only hypertension
but also various metabolic and vascular diosorders.
CONCLUSION
Adiponectin functions as an important adipocytokine link-
ing between adipose tissue and the vasculature. Adiponectin
directly acts on vascular endothelial cells and exerts salutary
eects on endothelial function through eNOS-dependent
and COX-2-dependent regulatory mechanisms. Adiponectin
can serve as a regulator of macrophage function and favor
anti- inammatory phenotype in macrophages, potentially
contributing to vascular protective properties. Clinical and
experimental studies indicate the causal relationship between
hypoadiponectinemia and hypertension. Blockade of angi-
otensin II type 1 receptor leads to elevation of circulating adi-
ponectin levels, which could confer the benecial pleiotropic
eects of ARBs including improvement of metabolic and
vascular function beyond antihypertensive actions. us, the
therapeutic strategies that enhance adiponectin production
or action have potential utility for prevention or treatment of
obesity-related vascular dysfunction such as hypertension.
Taken together, future studies are required to elucidate the
molecular and cellular mechanisms of adiponectin regulation
and function in more detail for comprehensive understanding
of the pathogenesis of metabolic syndrome.
Disclosure: The authors declared no conflict of interest.
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