Abstract

Obesity is strongly associated with the pathogenesis of type 2 diabetes, hypertension, and cardiovascular disease. Levels of the hormone adiponectin are downregulated in obese individuals, and several experimental studies show that adiponectin protects against the development of various obesity-related metabolic and cardiovascular diseases. Adiponectin exhibits favorable effects on atherogenesis, endothelial function, and vascular remodeling by modulation of signaling cascades in cells of the vasculature. More recent findings have shown that adiponectin directly affects signaling in cardiac cells and is beneficial in the setting of pathological cardiac remodeling and acute cardiac injury. Several of these effects of adiponectin have been attributed to the activation of the 5′ AMP-activated protein kinase signaling cascade and other signaling proteins. This review will discuss the epidemiological and experimental studies that have elucidated the role of adiponectin in a variety of cardiovascular diseases.

1. Introduction

Considerable effort has been directed at understanding the mechanisms of obesity in the pathogenesis of cardiovascular disease. This research has led to the concept that adipose tissue is more than just a simple energy storage compartment, but is also an important secretory organ for bioactive molecules referred to as adipokines. Adipokines contribute to the pathophysiology of obesity-linked disorders through their abilities to modulate inflammatory and metabolic processes. Levels of several adipokines (including leptin, tumor necrosis factor-α (TNF-α), plasminogen activator inhibitor type 1, interleukin-1β (IL-1β), IL-6, and IL-8) increase in obesity and tend to function in a pro-inflammatory manner [1,2]. In contrast, levels of adiponectin decrease in obese subjects and this adipokine functions to inhibit inflammatory processes. Clinical and experimental studies suggest that low adiponectin levels contribute to the development of obesity-linked illness including cardiovascular disease, insulin resistance and inflammation. This review focuses on the actions of adiponectin on the cardiovascular system in association with obesity-linked disorders.

Adiponectin, also referred to as ACRP30, AdipoQ and gelatin-binding protein-28 [3–5], is produced in adipocytes and accounts for as much as 0.01% of total plasma protein [6]. The primary protein sequence of adiponectin contains a collagen-like domain at the N terminus and a globular domain at the C terminus, similar to collagens VIII, X and complement factor C1q. The 30 kDa monomers of adiponectin have been shown to aggregate into several polymeric forms in human and mouse plasma, including trimeric, hexameric, and high-molecular weight oligomeric forms [7,8]. In addition to oligomers, adiponectin can also be processed by proteolysis, and a smaller globular domain fragment can be detected in plasma [9]. These various forms of adiponectin are postulated to have distinct signaling effects in the cardiovascular system [7,10,11].

Epidemiological studies on adiponectin

The role of adiponectin in obesity, diabetes and cardiovascular disease has been examined through several epidemiological studies discussed below.

Obesity

Total plasma adiponectin levels typically range from 3–30 μg/ml, in normal human subjects [6,12]. However, levels of adiponectin are significantly reduced in obese subjects compared to non-obese subjects, such that a significant negative correlation is found between body mass index (BMI) and plasma adiponectin levels [6,13]. Adiponectin concentrations have been negatively correlated with percent body fat, waist-to-hip ratio and intra-abdominal fat [13–15]. The reason for this reduction in adiponectin in obese subjects remains unclear but it may be due to either transcriptional suppression or decreased secretion caused by inflammatory cytokines. For example, pro-inflammatory cytokines (such as IL-6) are upregulated in the obese state and cause both a decrease in adiponectin mRNA and a reduction in adiponectin secretion from 3T3-L1 adipocytes [12,16].

Type 2 diabetes

Studies have addressed the role of adiponectin in type 2 diabetes, a disease that is common to the obese population. Plasma adiponectin levels are lower in patients with type 2 diabetes than in nondiabetic controls among subjects with similar body mass indices [17]. Similarly, individuals with higher adiponectin concentrations appear to be at a lower risk for developing type 2 diabetes [18,19]. In accordance with these findings, other clinical studies indicate that increasing adiponectin is a negative predictor of the development of insulin resistance and type 2 diabetes in BMI-adjusted subjects populations [20–22].

Cardiovascular disease

The role of adiponectin in the development of cardiac disease remains less clear than it does for metabolic disorders. While some studies indicate that low adiponectin levels are associated with cardiovascular disease, not all studies have been able to show such an association. For example, it has been reported that plasma adiponectin concentrations are lower in patients with clinical manifestations of coronary artery disease than in age- and BMI-adjusted control subjects independent of other risk factors [23–25]. High plasma adiponectin levels are associated both with a lower risk of myocardial infarction in men [26] and a moderately decreased risk for coronary heart disease in male diabetic patients [27]. Adiponectin levels are also reported to rapidly decline following acute myocardial infarction [28]. Collectively, these studies suggest that hypoadiponectinemia is associated with the development of cardiovascular diseases that are prevalent in obese individuals. Consistent with this notion, circulating adiponectin levels are inversely correlated with other cardiovascular risk factors, including hyperlipidemia, high blood pressure and C-reactive protein (CRP) levels [12,29,30]. However, other studies have not been able to draw a link between adiponectin levels and cardiovascular disease status. An association between plasma adiponectin concentrations and the risk of coronary heart disease could not be demonstrated in three recent prospective studies: (i) in the Strong Heart Study, plasma adiponectin levels did not correlate well with the incidence of coronary heart disease [31], (ii) despite a strong correlation of adiponectin levels with adiposity in the British Women's Heart Health Study, adiponectin levels were not predictive of coronary heart disease [32] and (iii) in a large study in British men with coronary heart disease combined with a meta-analysis of previously published prospective studies, the association between adiponectin levels and the risk of coronary heart disease was weak [33]. Therefore, the role of adiponectin in the development of coronary artery disease is controversial, and it appears that low levels of adiponectin will not be a reliable marker for this disease. One explanation for the discrepancy between studies is that heart disease will contribute to impaired renal function and this will confound the analysis due to a reduction in adiponectin clearance by the kidney.

Since hypertrophic cardiomyopathy and pathological cardiac remodeling are also associated with obesity [34,35], the potential role of adiponectin in hypertrophic cardiomyopathy has been analyzed. Low levels of adiponectin are associated with a further progression of left ventricular hypertrophy in patients presenting with hypertension, left ventricular diastolic dysfunction and hypertrophy [36].

Finally, adiponectin levels may influence the development of chronic heart failure, but the epidemiological data are somewhat complex. This is due in part to the fact that while higher body mass indices are a risk factor for heart failure, obesity is a predictor of improved prognoses in patients with established chronic heart failure because wasting is strongly associated with the increased risk of death in the final stages of this disease [37]. In this regard, high adiponectin levels are a predictor of mortality in patients with heart failure [38]. Presumably, this paradoxical relationship exists because high body mass, hence low adiponectin, favors survival in end-stage heart failure. Therefore, future studies should examine adiponectin levels in patients with stable heart failure.

Functional studies on adiponectin

A series of experiments in cell culture and animal models have shown that hypoadiponectinemia contributes to a variety of obesity-related diseases including diabetes, macro- and microvascular abnormalities and cardiac pathology (Fig. 1).

Fig. 1

Adiponectin is secreted by adipocytes and has a multiplicity of actions in the cardiovascular system. Adiponectin prevents insulin resistance by enhancing glucose and fatty acid disposal by skeletal muscle. In the heart, adiponectin prevents both pathological hypertrophy and ischemic injury, in part through the activation of AMPK. Adiponectin prevents atherosclerotic progression and intimal hyperplasia by reducing smooth muscle cell proliferation. Similarly, in microvessels and capillaries, adiponectin improves angiogenesis and endothelial function through actions on eNOS and blood vessel growth pathways.

Fig. 1

Adiponectin is secreted by adipocytes and has a multiplicity of actions in the cardiovascular system. Adiponectin prevents insulin resistance by enhancing glucose and fatty acid disposal by skeletal muscle. In the heart, adiponectin prevents both pathological hypertrophy and ischemic injury, in part through the activation of AMPK. Adiponectin prevents atherosclerotic progression and intimal hyperplasia by reducing smooth muscle cell proliferation. Similarly, in microvessels and capillaries, adiponectin improves angiogenesis and endothelial function through actions on eNOS and blood vessel growth pathways.

Glucose metabolism

Cardiovascular disease and insulin resistance are associated with several alterations in metabolism, including changes in the utilization of glucose. Insulin resistant tissues rely more on alternate sources of fuel, since glucose uptake is limited by an impairment of insulin action. High plasma glucose levels result from this decreased glucose disposal and often precede the development of Type II diabetes. Adiponectin has been shown to lower plasma glucose levels in mice, independent of changes in insulin levels [39], suggesting that adiponectin is important for insulin sensitivity. In addition, administration of adiponectin increases fatty acid oxidation in muscle and leads to a reduction in plasma free fatty acids, triglycerides and glucose [9]. These changes are suggestive of an insulin sensitizing action of adiponectin. Analyses of mice deficient for adiponectin confirm the role of adiponectin in insulin sensitivity. Adiponectin knockout (APN-KO) mice are viable and morphologically normal, however they exhibit diet-induced insulin resistance when fed a high fat/sucrose diet [40]. While these data support the notion that adiponectin functions to protect against the development of insulin resistance and diabetes, other strains of APN-KO mice exhibit different insulin-responsive phenotypes. For example, one line of APN-KO mice is reported to exhibit moderate insulin resistance when fed a normal chow diet [41], while another strain of adiponectin-deficient mice do not display this insulin resistant phenotype [42]. These data suggest that the relationships between adiponectin and insulin sensitivity are influenced by additional genetic loci that are currently unknown.

Adiponectin regulates metabolism and insulin sensitivity, at least in part, by promoting the phosphorylation and activation of AMP-activated protein kinase (AMPK) (a stress-responsive kinase) in skeletal muscle [43,44], liver [44] and adipocytes [45]. AMPK signaling affects many aspects of cellular metabolism including glucose uptake, glucose utilization and fatty acid oxidation. AMPK causes: (1) GLUT4 translocation to the cell surface to accelerate glucose uptake [46,47], (2) phosphorylation of phosphofructokinase-2 to enhance glycolytic disposal of glucose [48], and (3) phosphorylation and inactivation of acetyl CoA carboxylase, which leads to an increase in fatty acid oxidation rates [49,50]. AMPK activation is believed to be mediated by adiponectin binding to the cell surface receptors AdipoR1 and AdipoR2 [51]. Another adiponectin receptor (T-cadherin) has also been identified [52], but its role in activating AMPK and other intracellular signaling pathways remains unclear.

Atherosclerosis

Increasing evidence from experimental models indicates that adiponectin plays a pivotal role in the development of obesity-related vascular diseases including atherosclerosis. In the early stages of atherosclerosis, circulating monocytes adhere to activated endothelial cells (for a comprehensive review see [53]). Subsequently, monocytes differentiate into macrophages, leading to the accumulation of lipid rich foam cells by an uptake of modified lipoproteins. In vitro experiments show that adiponectin regulates many steps in this atherogenic process (Fig. 2). Adiponectin inhibits nuclear factor-κB (NF-κB) activation, effectively reducing: (i) TNF-α-stimulated monocyte adhesion to endothelial cells, (ii) TNF-α-stimulated expression of adhesion molecules and (iii) expression of the pro-inflammatory cytokine IL-8 in endothelial cells [54,55]. Adiponectin also inhibits the transformation of macrophages to foam cells and suppresses the expression of class A scavenger receptors in human macrophages [56]. Adiponectin reduces TNF-α production in human macrophages [57], and this effect may be mediated by its ability to suppress NF-κB signaling in this cell type [58,59]. Adiponectin also increases the expression of the anti-inflammatory cytokine IL-10 and the tissue inhibitor of metalloproteinase-1 in macrophages [60].

Fig. 2

Signaling pathways downstream of adiponectin in cells of the cardiovascular system. Adiponectin has anti-inflammatory effects due to suppression of NF-κB signaling in monocytes/macrophages and also reduces the progression of atherosclerotic lesions through suppression of NF-κB in endothelial cells. In addition, adiponectin signals through the AMPK pathway to reduce endothelial cell apoptosis and to promote nitric oxide production. In the heart, adiponectin activates AMPK and decreases the hypertrophic response through suppression of protein synthesis. COX-2 activation by adiponectin decreases expression of TNFα in the heart. Finally, adiponectin acts in smooth muscle cells to prevent atherosclerotic proliferation and migration of smooth muscle cells.

Fig. 2

Signaling pathways downstream of adiponectin in cells of the cardiovascular system. Adiponectin has anti-inflammatory effects due to suppression of NF-κB signaling in monocytes/macrophages and also reduces the progression of atherosclerotic lesions through suppression of NF-κB in endothelial cells. In addition, adiponectin signals through the AMPK pathway to reduce endothelial cell apoptosis and to promote nitric oxide production. In the heart, adiponectin activates AMPK and decreases the hypertrophic response through suppression of protein synthesis. COX-2 activation by adiponectin decreases expression of TNFα in the heart. Finally, adiponectin acts in smooth muscle cells to prevent atherosclerotic proliferation and migration of smooth muscle cells.

In vivo experiments have shown that adenovirus-mediated adiponectin overexpression reduces the formation of atherosclerotic lesions in the aortic sinus of the apolipoprotein E knockout (ApoE-KO) mouse (a model of atherosclerosis) [61]. This anti-atherogenic action of adiponectin is accompanied by reductions in the expression of class A scavenger receptors, TNF-α and vascular cell adhesion molecule-1. In agreement with this finding, ApoE-KO mice that overexpress an adiponectin transgene are protected against the development of atherosclerosis compared to untreated ApoE-KO mice [62].

Angiogenesis and endothelial function

In addition to the actions of adiponectin on atherosclerosis in the vasculature, it has also been shown that adiponectin has effects on angiogenesis and endothelial function. Obesity and diabetes are associated with endothelial dysfunction, microvascular rarefaction and reduced collateralization [63–68], suggesting vascular abnormalities occur in the pathogenesis of these diseases. A series of in vitro and in vivo studies suggest that adiponectin has protective actions on endothelial cells, and may therefore protect against the pathogenic effects of obesity on vascular function. Similar to the effects of adiponectin in muscle, it has been suggested that adiponectin acts through the AMPK signaling pathway in the vasculature (Fig. 2).

AMPK has been identified as a regulator of endothelial cell nitric oxide synthase (eNOS) activation as well as a number of cellular responses that are important for angiogenesis [69–75]. More recently, it has been recognized that adiponectin-mediated activation of AMPK is important for endothelial function and angiogenesis. It has been shown that adiponectin stimulates nitric oxide production in endothelial cells through an AMPK-dependent phosphorylation and activation of eNOS [70,76]. Globular adiponectin increases eNOS expression/activity in endothelial cells and also improves OxLDL-induced suppression of eNOS activity [77,78]. These studies suggest that adiponectin may play a critical role in maintaining endothelial function and vascular tone. Further evidence supports this role for adiponectin since the APN-KO mice exhibit an impaired endothelial-dependent vasodilation on an atherogenic diet [79]. Adiponectin also has anti-apoptotic actions in endothelial cells that are dependent on the induction of AMPK signaling [80], and globular adiponectin is reported to inhibit angiotensin II-induced apoptosis in human endothelial cells [81].

In addition to the anti-apoptotic actions of adiponectin in the vasculature, evidence suggests that adiponectin promotes growth of new blood vessels. Adiponectin stimulates endothelial cell migration and differentiation into capillary-like structures in vitro through activation of AMPK signaling [70]. Adiponectin supplementation has also been shown to stimulate blood vessel growth in both mouse Matrigel plug implantation and rabbit corneal models of angiogenesis [70]. APN-KO mice display impaired recovery of hindlimb ischemia as evaluated by laser Doppler flow method and capillary density analyses, whereas adenovirus-mediated supplement of adiponectin accelerates angiogenic repair in both APN-KO and WT mice by promoting AMPK signaling [82].

Vascular remodeling

Adiponectin may also modulate smooth muscle cell (SMC) growth in the development and progression of vascular lesions (Fig. 2). In vitro studies have shown that adiponectin can suppress the proliferation of SMCs and inhibit their directed migration to platelet-derived growth factor-BB [83]. This study also showed that adiponectin inhibits growth factor-stimulated extracellular signal-regulated kinase (ERK) signaling in human aortic SMC. In another study, adiponectin was found to inhibit SMC proliferation through its ability to bind various growth factors and interfere with their ability to activate receptor-mediated cellular responses [84]. Therefore, adiponectin may impair growth signaling pathways in smooth muscle cells and prevent the proliferation of SMCs associated with vascular lesions. The results of in vivo studies are consistent with this proposed inhibition of SMC growth by adiponectin. For example, APN-KO mice exhibit increased neointimal hyperplasia and proliferation of SMCs following acute vascular injury [41,85]. Conversely, adenovirus-mediated adiponectin expression reduces the increase in neointimal thickening observed in APN-KO mice [85].

Hypertrophic cardiomyopathy

Recent experimental studies have shown that adiponectin influences cardiac remodeling and functions to suppress pathological cardiac growth. In response to pressure overload caused by aortic constriction, APN-KO mice have enhanced concentric cardiac hypertrophy and increased mortality [86,87]. Adenovirus-mediated delivery of adiponectin has been shown to attenuate this cardiac hypertrophic in response to pressure overload in APN-KO, wild-type and diabetic db/db mice [86]. APN-KO mice also exhibit increased cardiac hypertrophy in response to angiotensin II infusion, while adiponectin overexpression reduces the hypertrophy in this model [86].

Adiponectin's actions in the setting of cardiac hypertrophy can be attributed to the modulation of intracellular growth signals in cardiac cells, including the AMPK signaling cascade (Fig. 2). While AMPK activity increases through phosphorylation as the heart undergoes a pressure overload hypertrophy [88], this increase in AMPK phosphorylation is attenuated in APN-KO mice [86]. Experiments in rat neonatal cardiac myocytes show that adiponectin activates AMPK, and inhibits the hypertrophic response to α-adrenergic receptor stimulation [86]. The inhibition of hypertrophic growth by adiponectin can be reversed by transduction with dominant-negative AMPK, providing further evidence that adiponectin acts through the AMPK signaling cascade. Activation of AMPK has been shown to inhibit protein synthesis in cardiac myocytes, which is mediated by a decrease in p70S6 kinase phosphorylation and an increase in phosphorylation of eukaryotic elongation factor-2 [89]. These anti-hypertrophic actions of adiponectin on AMPK are thought to occur via the AdipoR1 and R2 receptors [90]. A number of studies have reported that both of these adiponectin receptors are expressed by cardiac myocytes and heart tissue [51,91–93].

Myocardial ischemia–reperfusion injury

Obesity-related disorders have a major impact on the incidence and severity of ischemic heart disease [94,95] and evidence suggests that adiponectin is cardioprotective in this setting. Adiponectin inhibits apoptosis in cardiac myocytes and fibroblasts that are exposed to hypoxia-reoxygenation stress [96]. Transduction with dominant-negative AMPK blocks the pro-survival actions of adiponectin, indicating that adiponectin inhibits cardiac cell apoptosis through AMPK-dependent signaling. Similarly, recent work from our group demonstrates that following ischemia–reperfusion, APN-KO mice develop larger infarcts than wild-type mice [96]. These larger infarcts were associated with increased myocardial cell apoptosis and TNF-α expression in the APN-KO mice. Adenovirus-mediated delivery of adiponectin diminished infarct size, myocardial apoptosis and TNF-α production in both APN-KO and wild-type mice. Of note, this study showed that the one-time administration of recombinant adiponectin protein, injected either 30 min before the induction of ischemia, during ischemia or 15 min after reperfusion, resulted in a reduction in infarct size. Thus, short-term administration of adiponectin may have practical clinical utility in the treatment of acute myocardial infarction through the activation of AMPK.

While many studies suggest that cardiac AMPK activation is protective, it is important to note that enhanced AMPK activity in the heart has been suggested to reduce recovery following ischemia/reperfusion injury of ex vivo working hearts. These studies show that AMPK activity and fatty acid oxidation rates rapidly increase during ischemia, which may lead to intracellular acidosis and cell death [49,50,97]. The metabolic role of adiponectin in the ex vivo working heart has not been clearly established, although globular adiponectin has been shown to accelerate fatty acid oxidation independent of AMPK signaling [98]. Therefore, further experiments are required to elucidate the mechanism of adiponectin in the setting of ischemia/reperfusion injury and the putative role of AMPK in cardiac recovery.

The protective action of adiponectin against myocardial ischemia–reperfusion injury also appears to be mediated by its ability to activate cyclooxygenase-2 (COX-2) in cardiac cells [96]. COX-2 and its metabolites have been shown to be required for late preconditioning and play important protective roles in myocardial ischemia–reperfusion damage [99–103]. Recent clinical trials reveal that treatment with selective COX-2 inhibitors resulted in an increased risk for cardiovascular complications [104,105], further implicating a role of COX-2 in protection against ischemia induced injury. The upregulation of COX-2 by adiponectin lead to an increase in prostaglandin E2 (PGE2) synthesis and an inhibition of lipopolysaccharide (LPS)-induced TNF-α production [96]. These findings in cardiac myocytes and fibroblasts are consistent with findings in monocytic cells [96,106,107]. Pharmacological inhibitors of the COX-2-PGE2 pathway were found to reverse the inhibitory effects of adiponectin on LPS-induced TNF-α production in cardiac cells [96]. Of note, COX-2 inhibition had no effects on adiponectin-mediated AMPK activation or inhibition of apoptosis in cultured cardiac cells [96]. As well, AMPK-inhibition had no effect on COX-2 induction by adiponectin or on the suppressive effect of adiponectin on TNF-α production caused by LPS [96]. These findings suggest that adiponectin protects the ischemic heart from injury through the activation of independent pathways involving both AMPK-mediated anti-apoptotic actions and COX-2-mediated anti-inflammatory actions (Fig. 2).

Viral myocarditis

Finally, the role of adiponectin in viral myocarditis has been explored using a mouse model [47]. Leptin-deficient, ob/ob mice inoculated with encephalomyocarditis virus develop severe myocarditis, which is associated with an increased number of apoptotic and infiltrating cells. This phenotype can be minimized by daily subcutaneous injection of adiponectin over an 8-day period, suggesting that treatment with adiponectin can inhibit the development of acute myocarditis.

Conclusion

Adiponectin is an adipose tissue-derived hormone that exhibits diverse protective properties on the heart and blood vessels (Fig. 1). Adiponectin may contribute to the regulation of vascular homeostasis by its ability to affect several signaling pathways in the vessel walls and modulate excess inflammatory responses (Fig. 2). In the heart, adiponectin serves as a regulator of cardiac injury through modulation of pro-survival reactions, cardiac energy metabolism and inhibition of hypertrophic remodeling. Many effects of adiponectin in the cardiovascular system correlate with the activation of both AMPK and COX-2. Further evaluation of the biologically active forms of adiponectin and the adiponectin receptor-mediated signaling events in cardiovascular tissues should lead to a better understanding of how obesity affects the cardiovascular system.

Acknowledgements

This work was supported by NIH grants HL86785, HL77774, HL81587 and AG15052 to K. Walsh. N. Ouchi was supported by a Department of Medicine Pilot Project Grant from Boston University. Post-doctoral fellowship support for T.A. Hopkins is provided by the Canadian Diabetes Association and the Alberta Heritage Foundation for Medical Research. R. Shibata was supported by grants from the American Heart Association Postdoctoral Fellowship Award, Northeast Affiliate. N. Ouchi is supported by an American Heart Association Scientist Development Grant, Northeast Affiliate.

References

[1]
Berg
A.H.
Scherer
P.E.
Adipose tissue, inflammation, and cardiovascular disease
Circ Res
 
2005
96
939
949
[2]
Yang
Q.
Graham
T.E.
Mody
N.
Preitner
F.
Peroni
O.D.
Zabolotny
J.M.
et al
Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes
Nature
 
2005
436
356
362
[3]
Hu
E.
Liang
P.
Spiegelman
B.M.
AdipoQ is a novel adipose-specific gene dysregulated in obesity
J Biol Chem
 
1996
271
10697
10703
[4]
Maeda
K.
Okubo
K.
Shimomura
I.
Funahashi
T.
Matsuzawa
Y.
Matsubara
K.
cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1)
Biochem Biophys Res Commun
 
1996
221
286
289
[5]
Scherer
P.E.
Williams
S.
Fogliano
M.
Baldini
G.
Lodish
H.F.
A novel serum protein similar to C1q, produced exclusively in adipocytes
J Biol Chem
 
1995
270
26746
26749
[6]
Arita
Y.
Kihara
S.
Ouchi
N.
Takahashi
M.
Maeda
K.
Miyagawa
J.
et al
Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity
Biochem Biophys Res Commun
 
1999
257
79
83
[7]
Pajvani
U.B.
Du
X.
Combs
T.P.
Berg
A.H.
Rajala
M.W.
Schulthess
T.
et al
Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications for metabolic regulation and bioactivity
J Biol Chem
 
2003
278
9073
9085
[8]
Kishida
K.
Nagaretani
H.
Kondo
H.
Kobayashi
H.
Tanaka
S.
Maeda
N.
et al
Disturbed secretion of mutant adiponectin associated with the metabolic syndrome
Biochem Biophys Res Commun
 
2003
306
286
292
[9]
Fruebis
J.
Tsao
T.S.
Javorschi
S.
Ebbets-Reed
D.
Erickson
M.R.
Yen
F.T.
et al
Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice
Proc Natl Acad Sci U S A
 
2001
98
2005
2010
[10]
Tsao
T.S.
Tomas
E.
Murrey
H.E.
Hug
C.
Lee
D.H.
Ruderman
N.B.
et al
Role of disulfide bonds in Acrp30/adiponectin structure and signaling specificity. Different oligomers activate different signal transduction pathways
J Biol Chem
 
2003
278
50810
50817
[11]
Tsao
T.S.
Murrey
H.E.
Hug
C.
Lee
D.H.
Lodish
H.F.
Oligomerization state-dependent activation of NF-kappa B signaling pathway by adipocyte complement-related protein of 30 kDa (Acrp30)
J Biol Chem
 
2002
277
29359
29362
[12]
Ouchi
N.
Kihara
S.
Funahashi
T.
Matsuzawa
Y.
Walsh
K.
Obesity, adiponectin and vascular inflammatory disease
Curr Opin Lipidol
 
2003
14
561
566
[13]
Cnop
M.
Havel
P.J.
Utzschneider
K.M.
Carr
D.B.
Sinha
M.K.
Boyko
E.J.
et al
Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex
Diabetologia
 
2003
46
459
469
[14]
Weyer
C.
Funahashi
T.
Tanaka
S.
Hotta
K.
Matsuzawa
Y.
Pratley
R.E.
et al
Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia
J Clin Endocrinol Metab
 
2001
86
1930
1935
[15]
Ryo
M.
Nakamura
T.
Kihara
S.
Kumada
M.
Shibazaki
S.
Takahashi
M.
et al
Adiponectin as a biomarker of the metabolic syndrome
Circ J
 
2004
68
975
981
[16]
Fasshauer
M.
Kralisch
S.
Klier
M.
Lossner
U.
Bluher
M.
Klein
J.
et al
Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes
Biochem Biophys Res Commun
 
2003
301
1045
1050
[17]
Hotta
K.
Funahashi
T.
Arita
Y.
Takahashi
M.
Matsuda
M.
Okamoto
Y.
et al
Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients
Arterioscler Thromb Vasc Biol
 
2000
20
1595
1599
[18]
Lindsay
R.S.
Funahashi
T.
Hanson
R.L.
Matsuzawa
Y.
Tanaka
S.
Tataranni
P.A.
et al
Adiponectin and development of type 2 diabetes in the Pima Indian population
Lancet
 
2002
360
57
58
[19]
Spranger
J.
Kroke
A.
Mohlig
M.
Bergmann
M.M.
Ristow
M.
Boeing
H.
et al
Adiponectin and protection against type 2 diabetes mellitus
Lancet
 
2003
361
226
228
[20]
Snehalatha
C.
Mukesh
B.
Simon
M.
Viswanathan
V.
Haffner
S.M.
Ramachandran
A.
Plasma adiponectin is an independent predictor of type 2 diabetes in Asian Indians
Diabetes Care
 
2003
26
3226
3229
[21]
Choi
K.M.
Lee
J.
Lee
K.W.
Seo
J.A.
Oh
J.H.
Kim
S.G.
et al
Serum adiponectin concentrations predict the developments of type 2 diabetes and the metabolic syndrome in elderly Koreans
Clin Endocrinol (Oxf)
 
2004
61
75
80
[22]
Yamamoto
Y.
Hirose
H.
Saito
I.
Nishikai
K.
Saruta
T.
Adiponectin, an adipocyte-derived protein, predicts future insulin resistance: two-year follow-up study in Japanese population
J Clin Endocrinol Metab
 
2004
89
87
90
[23]
Ouchi
N.
Kihara
S.
Arita
Y.
Maeda
K.
Kuriyama
H.
Okamoto
Y.
et al
Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin
Circulation
 
1999
100
2473
2476
[24]
Kumada
M.
Kihara
S.
Sumitsuji
S.
Kawamoto
T.
Matsumoto
S.
Ouchi
N.
et al
Association of hypoadiponectinemia with coronary artery disease in men
Arterioscler Thromb Vasc Biol
 
2003
23
85
89
[25]
Nakamura
Y.
Shimada
K.
Fukuda
D.
Shimada
Y.
Ehara
S.
Hirose
M.
et al
Implications of plasma concentrations of adiponectin in patients with coronary artery disease
Heart
 
2004
90
528
533
[26]
Pischon
T.
Girman
C.J.
Hotamisligil
G.S.
Rifai
N.
Hu
F.B.
Rimm
E.B.
Plasma adiponectin levels and risk of myocardial infarction in men
JAMA
 
2004
291
1730
1737
[27]
Schulze
M.B.
Shai
I.
Rimm
E.B.
Li
T.
Rifai
N.
Hu
F.B.
Adiponectin and future coronary heart disease events among men with type 2 diabetes
Diabetes
 
2005
54
534
539
[28]
Kojima
S.
Funahashi
T.
Sakamoto
T.
Miyamoto
S.
Soejima
H.
Hokamaki
J.
et al
The variation of plasma concentrations of a novel, adipocyte derived protein, adiponectin, in patients with acute myocardial infarction
Heart
 
2003
89
667
[29]
Iwashima
Y.
Katsuya
T.
Ishikawa
K.
Ouchi
N.
Ohishi
M.
Sugimoto
K.
et al
Hypoadiponectinemia is an independent risk factor for hypertension
Hypertension
 
2004
43
1318
1323
[30]
Ouchi
N.
Kihara
S.
Funahashi
T.
Nakamura
T.
Nishida
M.
Kumada
M.
et al
Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue
Circulation
 
2003
107
671
674
[31]
Lindsay
R.S.
Resnick
H.E.
Zhu
J.
Tun
M.L.
Howard
B.V.
Zhang
Y.
et al
Adiponectin and coronary heart disease: the Strong Heart Study
Arterioscler Thromb Vasc Biol
 
2005
25
e15
e16
[32]
Lawlor
D.A.
Davey Smith
G.
Ebrahim
S.
Thompson
C.
Sattar
N.
Plasma adiponectin levels are associated with insulin resistance, but do not predict future risk of coronary heart disease in women
J Clin Endocrinol Metab
 
2005
90
5677
5683
[33]

Sattar N., Wannamethee G., Sarwar N., Tchemova J., Cherry L., Wallace A.M. et al. Adiponectin and coronary heart disease: a prospective study and meta-analysis. Circulation in press.

[34]
Ilercil
A.
Devereux
R.B.
Roman
M.J.
Paranicas
M.
O'Grady
M.J.
Welty
T.K.
et al
Relationship of impaired glucose tolerance to left ventricular structure and function: the Strong Heart Study
Am Heart J
 
2001
141
992
998
[35]
Rutter
M.K.
Parise
H.
Benjamin
E.J.
Levy
D.
Larson
M.G.
Meigs
J.B.
et al
Impact of glucose intolerance and insulin resistance on cardiac structure and function: sex-related differences in the Framingham Heart Study
Circulation
 
2003
107
448
454
[36]
Hong
S.J.
Park
C.G.
Seo
H.S.
Oh
D.J.
Ro
Y.M.
Associations among plasma adiponectin, hypertension, left ventricular diastolic function and left ventricular mass index
Blood Press
 
2004
13
236
242
[37]
Anker
S.D.
Ponikowski
P.
Varney
S.
Chua
T.P.
Clark
A.L.
Webb-Peploe
K.M.
et al
Wasting as independent risk factor for mortality in chronic heart failure
Lancet
 
1997
349
1050
1053
[38]
Kistorp
C.
Faber
J.
Galatius
S.
Gustafsson
F.
Frystyk
J.
Flyvbjerg
A.
et al
Plasma adiponectin, body mass index, and mortality in patients with chronic heart failure
Circulation
 
2005
112
1756
1762
[39]
Nawrocki
A.R.
Rajala
M.W.
Tomas
E.
Pajvani
U.B.
Saha
A.K.
Trumbauer
M.E.
et al
Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists
J Biol Chem
 
2006
281
2654
2660
[40]
Maeda
N.
Shimomura
I.
Kishida
K.
Nishizawa
H.
Matsuda
M.
Nagaretani
H.
et al
Diet-induced insulin resistance in mice lacking adiponectin/ACRP30
Nat Med
 
2002
8
731
737
[41]
Kubota
N.
Terauchi
Y.
Yamauchi
T.
Kubota
T.
Moroi
M.
Matsui
J.
et al
Disruption of adiponectin causes insulin resistance and neointimal formation
J Biol Chem
 
2002
277
25863
25866
[42]
Ma
K.
Cabrero
A.
Saha
P.K.
Kojima
H.
Li
L.
Chang
B.H.
et al
Increased beta-oxidation but no insulin resistance or glucose intolerance in mice lacking adiponectin
J Biol Chem
 
2002
277
34658
34661
[43]
Tomas
E.
Tsao
T.S.
Saha
A.K.
Murrey
H.E.
Zhang Cc
C.
Itani
S.I.
et al
Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation
Proc Natl Acad Sci U S A
 
2002
99
16309
16313
[44]
Yamauchi
T.
Kamon
J.
Minokoshi
Y.
Ito
Y.
Waki
H.
Uchida
S.
et al
Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase
Nat Med
 
2002
8
1288
1295
[45]
Wu
X.
Motoshima
H.
Mahadev
K.
Stalker
T.J.
Scalia
R.
Goldstein
B.J.
Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes
Diabetes
 
2003
52
1355
1363
[46]
Russell
R.R.
III
Li
J.
Coven
D.L.
Pypaert
M.
Zechner
C.
Palmeri
M.
et al
AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury
J Clin Invest
 
2004
114
495
503
[47]
Li
J.
Miller
E.J.
Ninomiya-Tsuji
J.
Russell
R.R.
III
Young
L.H.
AMP-activated protein kinase activates p38 mitogen-activated protein kinase by increasing recruitment of p38 MAPK to TAB1 in the ischemic heart
Circ Res
 
2005
97
872
879
[48]
Marsin
A.S.
Bertrand
L.
Rider
M.H.
Deprez
J.
Beauloye
C.
Vincent
M.F.
et al
Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia
Curr Biol
 
2000
10
1247
1255
[49]
Kudo
N.
Gillespie
J.G.
Kung
L.
Witters
L.A.
Schulz
R.
Clanachan
A.S.
et al
Characterization of 5′AMP-activated protein kinase activity in the heart and its role in inhibiting acetyl-CoA carboxylase during reperfusion following ischemia
Biochim Biophys Acta
 
1996
1301
67
75
[50]
Makinde
A.O.
Gamble
J.
Lopaschuk
G.D.
Upregulation of 5′-AMP-activated protein kinase is responsible for the increase in myocardial fatty acid oxidation rates following birth in the newborn rabbit
Circ Res
 
1997
80
482
489
[51]
Yamauchi
T.
Kamon
J.
Ito
Y.
Tsuchida
A.
Yokomizo
T.
Kita
S.
et al
Cloning of adiponectin receptors that mediate antidiabetic metabolic effects
Nature
 
2003
423
762
769
[52]
Hug
C.
Wang
J.
Ahmad
N.S.
Bogan
J.S.
Tsao
T.S.
Lodish
H.F.
T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin
Proc Natl Acad Sci U S A
 
2004
101
10308
10313
[53]
Lusis
A.J.
Atherosclerosis
Nature
 
2000
407
233
241
[54]
Kobashi
C.
Urakaze
M.
Kishida
M.
Kibayashi
E.
Kobayashi
H.
Kihara
S.
et al
Adiponectin inhibits endothelial synthesis of interleukin-8
Circ Res
 
2005
97
1245
1252
[55]
Ouchi
N.
Kihara
S.
Arita
Y.
Okamoto
Y.
Maeda
K.
Kuriyama
H.
et al
Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway
Circulation
 
2000
102
1296
1301
[56]
Ouchi
N.
Kihara
S.
Arita
Y.
Nishida
M.
Matsuyama
A.
Okamoto
Y.
et al
Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages
Circulation
 
2001
103
1057
1063
[57]
Yokota
T.
Oritani
K.
Takahashi
I.
Ishikawa
J.
Matsuyama
A.
Ouchi
N.
et al
Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages
Blood
 
2000
96
1723
1732
[58]
Wulster-Radcliffe
M.C.
Ajuwon
K.M.
Wang
J.
Christian
J.A.
Spurlock
M.E.
Adiponectin differentially regulates cytokines in porcine macrophages
Biochem Biophys Res Commun
 
2004
316
924
929
[59]
Yamaguchi
N.
Argueta
J.G.
Masuhiro
Y.
Kagishita
M.
Nonaka
K.
Saito
T.
et al
Adiponectin inhibits Toll-like receptor family-induced signaling
FEBS Lett
 
2005
579
6821
6826
[60]
Kumada
M.
Kihara
S.
Ouchi
N.
Kobayashi
H.
Okamoto
Y.
Ohashi
K.
et al
Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages
Circulation
 
2004
109
2046
2049
[61]
Okamoto
Y.
Kihara
S.
Ouchi
N.
Nishida
M.
Arita
Y.
Kumada
M.
et al
Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice
Circulation
 
2002
106
2767
2770
[62]
Yamauchi
T.
Kamon
J.
Waki
H.
Imai
Y.
Shimozawa
N.
Hioki
K.
et al
Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis
J Biol Chem
 
2003
278
2461
2468
[63]
Waltenberger
J.
Impaired collateral vessel development in diabetes: potential cellular mechanisms and therapeutic implications
Cardiovasc Res
 
2001
49
554
560
[64]
Noon
J.P.
Walker
B.R.
Webb
D.J.
Shore
A.C.
Holton
D.W.
Edwards
H.V.
et al
Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure
J Clin Invest
 
1997
99
1873
1879
[65]
Yilmaz
M.B.
Biyikoglu
S.F.
Akin
Y.
Guray
U.
Kisacik
H.L.
Korkmaz
S.
Obesity is associated with impaired coronary collateral vessel development
Int J Obes Relat Metab Disord
 
2003
27
1541
1545
[66]
Lind
L.
Lithell
H.
Decreased peripheral blood flow in the pathogenesis of the metabolic syndrome comprising hypertension, hyperlipidemia, and hyperinsulinemia
Am Heart J
 
1993
125
1494
1497
[67]
Steinberg
H.O.
Chaker
H.
Leaming
R.
Johnson
A.
Brechtel
G.
Baron
A.D.
Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance
J Clin Invest
 
1996
97
2601
2610
[68]
Al Suwaidi
J.
Higano
S.T.
Holmes
D.R.
Jr.
Lennon
R.
Lerman
A.
Obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries
J Am Coll Cardiol
 
2001
37
1523
1528
[69]
Chen
Z.P.
Mitchelhill
K.I.
Michell
B.J.
Stapleton
D.
Rodriguez-Crespo
I.
Witters
L.A.
et al
AMP-activated protein kinase phosphorylation of endothelial NO synthase
FEBS Lett
 
1999
443
285
289
[70]
Ouchi
N.
Kobayashi
H.
Kihara
S.
Kumada
M.
Sato
K.
Inoue
T.
et al
Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells
J Biol Chem
 
2004
279
1304
1309
[71]
Nagata
D.
Mogi
M.
Walsh
K.
AMP-activated protein kinase (AMPK) signaling in endothelial cells is essential for angiogenesis in response to hypoxic stress
J Biol Chem
 
2003
278
31000
31006
[72]
Yun
H.
Lee
M.
Kim
S.S.
Ha
J.
Glucose deprivation increases mRNA stability of vascular endothelial growth factor through activation of AMP-activated protein kinase in DU145 prostate carcinoma
J Biol Chem
 
2005
280
9963
9972
[73]
Ouchi
N.
Shibata
R.
Walsh
K.
AMP-activated protein kinase signaling stimulates VEGF expression and angiogenesis in skeletal muscle
Circ Res
 
2005
96
838
846
[74]
Treins
C.
Murdaca
J.
Van Obberghen
E.
Giorgetti-Peraldi
S.
AMPK activation inhibits the expression of HIF-1alpha induced by insulin and IGF-1
Biochem Biophys Res Commun
 
2006
342
1197
1202
[75]
Neurath
K.M.
Keough
M.P.
Mikkelsen
T.
Claffey
K.P.
AMP-dependent protein kinase alpha 2 isoform promotes hypoxia-induced VEGF expression in human glioblastoma
Glia
 
2006
53
733
743
[76]
Chen
H.
Montagnani
M.
Funahashi
T.
Shimomura
I.
Quon
M.J.
Adiponectin stimulates production of nitric oxide in vascular endothelial cells
J Biol Chem
 
2003
278
45021
45026
[77]
Hattori
Y.
Suzuki
M.
Hattori
S.
Kasai
K.
Globular adiponectin upregulates nitric oxide production in vascular endothelial cells
Diabetologia
 
2003
46
1543
1549
[78]
Motoshima
H.
Wu
X.
Mahadev
K.
Goldstein
B.J.
Adiponectin suppresses proliferation and superoxide generation and enhances eNOS activity in endothelial cells treated with oxidized LDL
Biochem Biophys Res Commun
 
2004
315
264
271
[79]
Ouchi
N.
Ohishi
M.
Kihara
S.
Funahashi
T.
Nakamura
T.
Nagaretani
H.
et al
Association of hypoadiponectinemia with impaired vasoreactivity
Hypertension
 
2003
42
231
234
[80]
Kobayashi
H.
Ouchi
N.
Kihara
S.
Walsh
K.
Kumada
M.
Abe
Y.
et al
Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin
Circ Res
 
2004
94
e27
e31
[81]
Lin
L.Y.
Lin
C.Y.
Su
T.C.
Liau
C.S.
Angiotensin II-induced apoptosis in human endothelial cells is inhibited by adiponectin through restoration of the association between endothelial nitric oxide synthase and heat shock protein 90
FEBS Lett
 
2004
574
106
110
[82]
Shibata
R.
Ouchi
N.
Kihara
S.
Sato
K.
Funahashi
T.
Walsh
K.
Adiponectin stimulates angiogenesis in response to tissue ischemia through stimulation of Amp-activated protein kinase signaling
J Biol Chem
 
2004
279
28670
28674
[83]
Arita
Y.
Kihara
S.
Ouchi
N.
Maeda
K.
Kuriyama
H.
Okamoto
Y.
et al
Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell
Circulation
 
2002
105
2893
2898
[84]
Wang
Y.
Lam
K.S.
Xu
J.Y.
Lu
G.
Xu
L.Y.
Cooper
G.J.
et al
Adiponectin inhibits cell proliferation by interacting with several growth factors in an oligomerization-dependent manner
J Biol Chem
 
2005
280
18341
18347
[85]
Matsuda
M.
Shimomura
I.
Sata
M.
Arita
Y.
Nishida
M.
Maeda
N.
et al
Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis
J Biol Chem
 
2002
277
37487
37491
[86]
Shibata
R.
Ouchi
N.
Ito
M.
Kihara
S.
Shiojima
I.
Pimentel
D.R.
et al
Adiponectin-mediated modulation of hypertrophic signals in the heart
Nat Med
 
2004
10
1384
1389
[87]
Liao
Y.
Takashima
S.
Maeda
N.
Ouchi
N.
Komamura
K.
Shimomura
I.
et al
Exacerbation of heart failure in adiponectin-deficient mice due to impaired regulation of AMPK and glucose metabolism
Cardiovasc Res
 
2005
67
705
713
[88]
Tian
R.
Musi
N.
D'Agostino
J.
Hirshman
M.F.
Goodyear
L.J.
Increased adenosine monophosphate-activated protein kinase activity in rat hearts with pressure-overload hypertrophy
Circulation
 
2001
104
1664
1669
[89]
Chan
A.Y.
Soltys
C.L.
Young
M.E.
Proud
C.G.
Dyck
J.R.
Activation of AMP-activated protein kinase inhibits protein synthesis associated with hypertrophy in the cardiac myocyte
J Biol Chem
 
2004
279
32771
32779
[90]
Fujioka
D.
Kawabata
K.
Saito
Y.
Kobayashi
T.
Nakamura
T.
Kodama
Y.
et al
Role of adiponectin receptors in endothelin-induced cellular hypertrophy in cultured cardiomyocytes and their expression in infarcted heart
Am J Physiol Heart Circ Physiol
 
2006
290
H2409
H2416
[91]
Ivanov
D.
Philippova
M.
Antropova
J.
Gubaeva
F.
Iljinskaya
O.
Tararak
E.
et al
Expression of cell adhesion molecule T-cadherin in the human vasculature
Histochem Cell Biol
 
2001
115
231
242
[92]
Lord
E.
Ledoux
S.
Murphy
B.D.
Beaudry
D.
Palin
M.F.
Expression of adiponectin and its receptors in swine
J Anim Sci
 
2005
83
565
578
[93]
Takahashi
T.
Saegusa
S.
Sumino
H.
Nakahashi
T.
Iwai
K.
Morimoto
S.
et al
Adiponectin, T-cadherin and tumour necrosis factor-alpha in damaged cardiomyocytes from autopsy specimens
J Int Med Res
 
2005
33
236
244
[94]
Wolk
R.
Berger
P.
Lennon
R.J.
Brilakis
E.S.
Somers
V.K.
Body mass index: a risk factor for unstable angina and myocardial infarction in patients with angiographically confirmed coronary artery disease
Circulation
 
2003
108
2206
2211
[95]
Orlander
P.R.
Goff
D.C.
Morrissey
M.
Ramsey
D.J.
Wear
M.L.
Labarthe
D.R.
et al
The relation of diabetes to the severity of acute myocardial infarction and post-myocardial infarction survival in Mexican–Americans and non-Hispanic whites. The Corpus Christi Heart Project
Diabetes
 
1994
43
897
902
[96]
Shibata
R.
Sato
K.
Pimentel
D.R.
Takemura
Y.
Kihara
S.
Ohashi
K.
et al
Adiponectin protects against myocardial ischemia–reperfusion injury through AMPK- and COX-2-dependent mechanisms
Nat Med
 
2005
11
1096
1103
[97]
Kudo
N.
Barr
A.J.
Barr
R.L.
Desai
S.
Lopaschuk
G.D.
High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5′-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase
J Biol Chem
 
1995
270
17513
17520
[98]
Onay-Besikci
A.
Altarejos
J.Y.
Lopaschuk
G.D.
gAd-globular head domain of adiponectin increases fatty acid oxidation in newborn rabbit hearts
J Biol Chem
 
2004
279
44320
44326
[99]
Bolli
R.
Shinmura
K.
Tang
X.L.
Kodani
E.
Xuan
Y.T.
Guo
Y.
et al
Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning
Cardiovasc Res
 
2002
55
506
519
[100]
Camitta
M.G.
Gabel
S.A.
Chulada
P.
Bradbury
J.A.
Langenbach
R.
Zeldin
D.C.
et al
Cyclooxygenase-1 and-2 knockout mice demonstrate increased cardiac ischemia/reperfusion injury but are protected by acute preconditioning
Circulation
 
2001
104
2453
2458
[101]
Xiao
C.Y.
Yuhki
K.
Hara
A.
Fujino
T.
Kuriyama
S.
Yamada
T.
et al
Prostaglandin E2 protects the heart from ischemia–reperfusion injury via its receptor subtype EP4
Circulation
 
2004
109
2462
2468
[102]
Hohlfeld
T.
Meyer-Kirchrath
J.
Vogel
Y.C.
Schror
K.
Reduction of infarct size by selective stimulation of prostaglandin EP(3)receptors in the reperfused ischemic pig heart
J Mol Cell Cardiol
 
2000
32
285
296
[103]
Xiao
C.Y.
Hara
A.
Yuhki
K.
Fujino
T.
Ma
H.
Okada
Y.
et al
Roles of prostaglandin I(2) and thromboxane A(2) in cardiac ischemia–reperfusion injury: a study using mice lacking their respective receptors
Circulation
 
2001
104
2210
2215
[104]
Solomon
S.D.
McMurray
J.J.
Pfeffer
M.A.
Wittes
J.
Fowler
R.
Finn
P.
et al
Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention
N Engl J Med
 
2005
352
1071
1080
[105]
Bresalier
R.S.
Sandler
R.S.
Quan
H.
Bolognese
J.A.
Oxenius
B.
Horgan
K.
et al
Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial
N Engl J Med
 
2005
352
1092
1102
[106]
Meja
K.K.
Barnes
P.J.
Giembycz
M.A.
Characterization of the prostanoid receptor(s) on human blood monocytes at which prostaglandin E2 inhibits lipopolysaccharide-induced tumour necrosis factor-alpha generation
Br J Pharmacol
 
1997
122
149
157
[107]
Pruimboom
W.M.
van Dijk
J.A.
Tak
C.J.
Garrelds
I.
Bonta
I.L.
Wilson
P.J.
et al
Interactions between cytokines and eicosanoids: a study using human peritoneal macrophages
Immunol Lett
 
1994
41
255
260

Author notes

Time for primary review 22 days