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  • Review Article
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Protective vascular and myocardial effects of adiponectin

Nature Clinical Practice Cardiovascular Medicine volume 6, pages 27–35 (2009)Cite this article

Abstract

Adiponectin is an abundant plasma protein secreted from adipocytes that elicits protective effects in the vasculature and myocardium. In obesity and insulin-resistant states, adiponectin levels are reduced and loss of its protective effects might contribute to the excess cardiovascular risk observed in these conditions. Adiponectin ameliorates the progression of macrovascular disease in rodent models, consistent with its correlation with improved vascular outcomes in epidemiological studies. The mechanisms of adiponectin signaling are multiple and vary among its cellular sites of action. In endothelial cells, adiponectin enhances production of nitric oxide, suppresses production of reactive oxygen species, and protects cells from inflammation that results from exposure to high glucose levels or tumor necrosis factor, through activation of AMP-activated protein kinase and cyclic AMP-dependent protein kinase (also known as protein kinase A) signaling cascades. In the myocardium, adiponectin-mediated protection from ischemia–reperfusion injury is linked to cyclo-oxygenase-2-mediated suppression of tumor necrosis factor signaling, inhibition of apoptosis by AMP-activated protein kinase, and inhibition of excess peroxynitrite-induced oxidative and nitrative stress. In this Review, we provide an update of studies of the signaling effects of adiponectin in endothelial cells and cardiomyocytes.

Key Points

  • Adiponectin is an abundant plasma protein secreted from adipocytes that elicits salutary effects in the vasculature and myocardium

  • The mechanisms of adiponectin signaling are multiple and vary among its cellular sites of action

  • In endothelial cells, adiponectin enhances nitric oxide, suppresses oxidative stress and suppresses the inflammatory signaling cascades via AMP-activated protein kinases and the cyclic AMP–protein kinase A-linked pathway

  • In the myocardium, adiponectin reduces ischemia–reperfusion injury via COX-2-mediated suppression of tumor necrosis factor signaling, AMP-activated protein kinases, and inhibition of excess peroxynitrite-induced oxidative and nitrative stress

  • Further work is necessary to elucidate the role of oligomeric forms of adiponectin in the heart and vasculature and their potential therapeutic value

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Figure 1: Structure of adiponectin.
Figure 2: Adiponectin signal-transduction pathways suppress endothelial cell activation elicited by high glucose levels and agonists such as TNF.
Figure 3: Adiponectin signaling in cardiomyocytes.

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References

  1. Goldstein BJ and Scalia R (2007) Adipokines and vascular disease in diabetes. Curr Diab Rep 7: 25–33

    Article  CAS  Google Scholar 

  2. Zhu W et al. (2008) Vascular effects of adiponectin: molecular mechanisms and potential therapeutic intervention. Clin Sci (Lond) 114: 361–374

    Article  CAS  Google Scholar 

  3. Jay D et al. (2006) Oxidative stress and diabetic cardiovascular complications. Free Radic Biol Med 40: 183–192

    Article  CAS  Google Scholar 

  4. Granger DN et al. (2004) Modulation of the inflammatory response in cardiovascular disease. Hypertension 43: 924–931

    Article  CAS  Google Scholar 

  5. Ouchi N et al. (2003) Association of hypoadiponectinemia with impaired vasoreactivity. Hypertension 42: 231–234

    Article  CAS  Google Scholar 

  6. Shimabukuro M et al. (2003) Hypoadiponectinemia is closely linked to endothelial dysfunction in man. J Clin Endocrinol Metab 88: 3236–3240

    Article  CAS  Google Scholar 

  7. Tan KC et al. (2004) Hypoadiponectinemia is associated with impaired endothelium-dependent vasodilation. J Clin Endocrinol Metab 89: 765–769

    Article  CAS  Google Scholar 

  8. Fernandez-Real JM et al. (2004) Adiponectin is associated with vascular function independent of insulin sensitivity. Diabetes Care 27: 739–745

    Article  CAS  Google Scholar 

  9. Halperin F et al. (2005) The role of total and high-molecular-weight complex of adiponectin in vascular function in offspring whose parents both had type 2 diabetes. Diabetologia 48: 2147–2154

    Article  CAS  Google Scholar 

  10. Kubota N et al. (2002) Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 277: 25863–25866

    Article  CAS  Google Scholar 

  11. Matsuda M et al. (2002) Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis. J Biol Chem 277: 37487–37491

    Article  CAS  Google Scholar 

  12. Okamoto Y et al. (2002) Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 106: 2767–2770

    Article  CAS  Google Scholar 

  13. Yamauchi T et al. (2003) Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem 278: 2461–2468

    Article  CAS  Google Scholar 

  14. Ohashi K et al. (2006) Adiponectin replenishment ameliorates obesity-related hypertension. Hypertension 47: 1108–1116

    Article  CAS  Google Scholar 

  15. Okamoto Y et al. (2000) An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls. Horm Metab Res 32: 47–50

    Article  CAS  Google Scholar 

  16. Shibata R et al. (2005) Adiponectin protects against myocardial ischemia–reperfusion injury through AMP kinase- and COX-2-dependent mechanisms. Nat Med 11: 1096–1103

    Article  CAS  Google Scholar 

  17. Tao L et al. (2007) Adiponectin cardioprotection after myocardial ischemia/reperfusion involves the reduction of oxidative/nitrative stress. Circulation 115: 1408–1416

    Article  CAS  Google Scholar 

  18. Scherer PE (2006) Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes 55: 1537–1545

    Article  CAS  Google Scholar 

  19. Wang Y et al. (2002) Hydroxylation and glycosylation of the four conserved lysine residues in the collagenous domain of adiponectin. Potential role in the modulation of its insulin-sensitizing activity. J Biol Chem 277: 19521–19529

    Article  CAS  Google Scholar 

  20. Pajvani UB et al. (2003) Structure–function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications for metabolic regulation and bioactivity. J Biol Chem 278: 9073–9085

    Article  CAS  Google Scholar 

  21. Schraw T et al. (2008) Plasma adiponectin complexes have distinct biochemical characteristics. Endocrinology 149: 2270–2282

    Article  CAS  Google Scholar 

  22. Neumeier M et al. (2006) Different effects of adiponectin isoforms in human monocytic cells. J Leukoc Biol 79: 803–808

    Article  CAS  Google Scholar 

  23. Fruebis J et al. (2001) 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 USA 98: 2005–2010

    Article  CAS  Google Scholar 

  24. Ouedraogo R et al. (2007) Adiponectin deficiency increases leukocyte–endothelium interactions via upregulation of endothelial cell adhesion molecules in vivo. J Clin Invest 117: 1718–1726

    Article  CAS  Google Scholar 

  25. Hopkins TA et al. (2006) Adiponectin actions in the cardiovascular system. Cardiovasc Res 74: 11–18

    Article  Google Scholar 

  26. Waki H et al. (2005) Generation of globular fragment of adiponectin by leukocyte elastase secreted by monocytic cell line THP-1. Endocrinology 146: 790–796

    Article  CAS  Google Scholar 

  27. Kadowaki T et al. (2006) Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 116: 1784–1792

    Article  CAS  Google Scholar 

  28. Ouedraogo R et al. (2006) Adiponectin suppression of high-glucose-induced reactive oxygen species in vascular endothelial cells: evidence for involvement of a cAMP signaling pathway. Diabetes 55: 1840–1846

    Article  CAS  Google Scholar 

  29. Motoshima H et al. (2004) Adiponectin suppresses proliferation and superoxide generation and enhances eNOS activity in endothelial cells treated with oxidized LDL. Biochem Biophys Res Commun 315: 264–271

    Article  CAS  Google Scholar 

  30. Ding G et al. (2007) Adiponectin and its receptors are expressed in adult ventricular cardiomyocytes and upregulated by activation of peroxisome proliferator-activated receptor γ. J Mol Cell Cardiol 43: 73–84

    Article  CAS  Google Scholar 

  31. Hug C et al. (2004) T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin. Proc Natl Acad Sci USA 101: 10308–10313

    Article  CAS  Google Scholar 

  32. Williams JK et al. (1988) Vasa vasorum in atherosclerotic coronary arteries: responses to vasoactive stimuli and regression of atherosclerosis. Circ Res 62: 515–523

    Article  CAS  Google Scholar 

  33. Herrmann J et al. (2001) Coronary vasa vasorum neovascularization precedes epicardial endothelial dysfunction in experimental hypercholesterolemia. Cardiovasc Res 51: 762–766

    Article  CAS  Google Scholar 

  34. Libby P (2002) Inflammation in atherosclerosis. Nature 420: 868–874

    Article  CAS  Google Scholar 

  35. Moulton KS (2006) Angiogenesis in atherosclerosis: gathering evidence beyond speculation. Curr Opin Lipidol 17: 548–555

    Article  CAS  Google Scholar 

  36. Lautamaki R et al. (2007) Low serum adiponectin is associated with high circulating oxidized low-density lipoprotein in patients with type 2 diabetes mellitus and coronary artery disease. Metabolism 56: 881–886

    Article  Google Scholar 

  37. Furukawa S et al. (2004) Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114: 1752–1761

    Article  CAS  Google Scholar 

  38. Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54: 1615–1625

    Article  CAS  Google Scholar 

  39. Rask-Madsen C and King GL (2007) Mechanisms of disease: endothelial dysfunction in insulin resistance and diabetes. Nat Clin Pract Endocrinol Metab 3: 46–56

    Article  CAS  Google Scholar 

  40. Ouchi N et al. (1999) Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 100: 2473–2476

    Article  CAS  Google Scholar 

  41. Ouchi N et al. (2000) Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway. Circulation 102: 1296–1301

    Article  CAS  Google Scholar 

  42. Xu SQ et al. (2008) Adiponectin protects against angiotensin II or tumor necrosis factor alpha-induced endothelial cell monolayer hyperpermeability: role of cAMP/PKA signaling. Arterioscler Thromb Vasc Biol 28: 899–905

    Article  CAS  Google Scholar 

  43. Chen H et al. (2003) Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem 278: 45021–45026

    Article  CAS  Google Scholar 

  44. Hattori Y et al. (2003) Globular adiponectin upregulates nitric oxide production in vascular endothelial cells. Diabetologia 46: 1543–1549

    Article  CAS  Google Scholar 

  45. Xi W et al. (2005) Stimulated HSP90 binding to eNOS and activation of the PI3-Akt pathway contribute to globular adiponectin-induced NO production: vasorelaxation in response to globular adiponectin. Biochem Biophys Res Commun 332: 200–205

    Article  CAS  Google Scholar 

  46. Kobayashi H et al. (2004) Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin. Circ Res 94: e27–e31

    Article  CAS  Google Scholar 

  47. Ouchi N et al. (2004) Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. J Biol Chem 279: 1304–1309

    Article  CAS  Google Scholar 

  48. Kadowaki T et al. (2007) The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS. FEBS Lett 582: 74–80

    Article  Google Scholar 

  49. Goldstein BJ and Scalia R (2004) Adiponectin: a novel adipokine linking adipocytes and vascular function. J Clin Endocrinol Metab 89: 2563–2568

    Article  CAS  Google Scholar 

  50. Wu X et al. (2007) Adiponectin suppresses IkappaB kinase activation induced by tumor necrosis factor-alpha or high glucose in endothelial cells: role of cAMP and AMP kinase signaling. Am J Physiol Endocrinol Metab 293: E1836–E1844

    Article  CAS  Google Scholar 

  51. Mahadev K et al. (2008) Adiponectin inhibits vascular endothelial growth factor-induced migration of human coronary artery endothelial cells. Cardiovasc Res 78: 376–384

    Article  CAS  Google Scholar 

  52. Collins SP et al. (2000) LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo. Biochem J 345: 673–680

    Article  CAS  Google Scholar 

  53. Shibata R (2004) Adiponectin stimulates angiogenesis in response to tissue ischemia through stimulation of AMP-activated protein kinase signaling. J Biol Chem 279: 28670–28674

    Article  CAS  Google Scholar 

  54. Brååkenhielm E et al. (2004) Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci USA 101: 2476–2481

    Article  Google Scholar 

  55. Bora PS et al. (2007) Expression of adiponectin in choroidal tissue and inhibition of laser induced choroidal neovascularization by adiponectin. FEBS Lett 58: 1977–1982

    Article  Google Scholar 

  56. Natarajan R et al. (2008) Hypoxia inducible factor-1 upregulates adiponectin in diabetic mouse hearts and attenuates post-ischemic injury. J Cardiovasc Pharmacol 51: 178–187

    Article  CAS  Google Scholar 

  57. Date H et al. (2006) Adiponectin produced in coronary circulation regulates coronary flow reserve in nondiabetic patients with angiographically normal coronary arteries. Clin Cardiol 29: 211–214

    Article  Google Scholar 

  58. Sharma K et al. (2008) Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest 118: 1645–1656

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Frystyk, J et al. (2005) Increased serum adiponectin levels in type 1 diabetic patients with microvascular complications. Diabetologia 48: 1911–1918

    Article  CAS  Google Scholar 

  60. Schalkwijk CG et al. (2005) Adiponectin is inversely associated with renal function in Type 1 diabetic patients. J Clin Endocrinol Metab 91: 129–135

    Article  Google Scholar 

  61. Koshimura J et al. (2004) Urinary adiponectin excretion is increased in patients with overt diabetic nephropathy. Biochem Biophys Res Commun 316: 165–169

    Article  CAS  Google Scholar 

  62. Shinmura K et al. (2007) Cardioprotective effects of short-term caloric restriction are mediated by adiponectin via activation of AMP-activated protein kinase. Circulation 116: 2809–2817

    Article  CAS  Google Scholar 

  63. Ikeda Y et al. (2008) Cyclooxygenase-2 induction by adiponectin is regulated by a sphingosine kinase-1 dependent mechanism in cardiac myocytes. FEBS Lett 582: 1147–1150

    Article  CAS  Google Scholar 

  64. Gao F et al. (2002) Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia–reperfusion: the roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation. Circulation 105: 1497–1502

    Article  CAS  Google Scholar 

  65. Li R et al. (2007) Adiponectin improves endothelial function in hyperlipidemic rats by reducing oxidative/nitrative stress and differential regulation of eNOS/iNOS activity. Am J Physiol Endocrinol Metab 293: E1703–E1708

    Article  CAS  Google Scholar 

  66. Kim YM et al. (1999) Nitric oxide as a bifunctional regulator of apoptosis. Circ Res 84: 253–256

    Article  CAS  Google Scholar 

  67. Beckman JS and Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271: C1424–C1437

    Article  CAS  Google Scholar 

  68. Ferdinandy P et al. (2000) Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res 87: 241–247

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. BJ Goldstein is Vice President of Clinical Research in Metabolism, Merck Research Laboratories, Rahway, NJ.,

    Barry J Goldstein

  2. RG Scalia is an Associate Professor in the Department of Molecular Physiology and Biophysics, and XL Ma is a Professor in the Department of Emergency Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA.,

    Rosario G Scalia & Xin L Ma

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  1. Barry J Goldstein
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  2. Rosario G Scalia
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  3. Xin L Ma
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Correspondence to Rosario G Scalia or Xin L Ma.

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Goldstein, B., Scalia, R. & Ma, X. Protective vascular and myocardial effects of adiponectin. Nat Rev Cardiol 6, 27–35 (2009). https://doi.org/10.1038/ncpcardio1398

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