Cardiovascular disease accounts for an overwhelming proportion of the morbidity and mortality suffered by patients with diabetes mellitus. Insulin resistance in obesity and type 2 diabetes, characterized by excess circulating non-esterified fatty acids (NEFA) and cytokines such as TNFalpha, and the hyperglycemia of overt diabetes are associated with endothelial dysfunction that contributes to the atherosclerotic process. Adiponectin is an abundant plasma protein secreted from adipose tissue that exhibits potent anti-inflammatory effects in the vasculature as well as insulin-sensitizing properties in metabolically-active tissues. In extensive preliminary studies, we have made the novel observations that the recombinant globular domain of adiponectin (gAd) exhibits a number of salutary effects in cultured endothelial cells, including enhanced nitric oxide (NO) production associated with activation of AMP kinase, and reduced superoxide generation induced by oxidized LDL (oxLDL) which is associated with cellular NAD(P)H oxidase activity. In addition, gAd inhibits superoxide production in endothelial cells exposed to high glucose, blocks the oxidation of native LDL by endothelial cells, and suppresses cell proliferation and MAP kinase activation stimulated by oxLDL. By quantitative intravital microscopy in the db/db mouse, we have also found in our initial studies that overexpression of gAd by adenoviral gene delivery in vivo ameliorates the increased leukocyte/endothelial interactions characteristic of the endothelial dysfunction in this model of insulin resistant type 2 diabetes. We propose here to combine studies of endothelial cells in vitro with intravital microscopy in situ to examine the cellular responses and signaling mechanisms of the two major forms of adiponectin (full-length and gAd) and test the hypotheses that adiponectin: (1) enhances NO production in states of endothelial dysfunction via an AMP kinase-linked pathway; (2) suppresses superoxide production by endothelial cells treated with oxLDL or high glucose, possibly via an NAD(P)H oxidase-linked pathway; and (3) ameliorates endothelial dysfunction in vivo in rodent models of obesity with insulin resistance and/or diabetes as evidenced by salutary effects on leukocyte/endothelial interactions, expression of cell adhesion molecules and NO production. These studies will provide insight into the cellular mechanisms employed by adiponectin to ameliorate endothelial dysfunction in states of insulin resistance and type 2 diabetes, and may lead to improved strategies to reduce the excessive cardiovascular risk associated with these disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Metabolism Study Section (MET)
Program Officer
Jones, Teresa L Z
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Thomas Jefferson University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Wang, Yajing; Gao, Erhe; Tao, Ling et al. (2009) AMP-activated protein kinase deficiency enhances myocardial ischemia/reperfusion injury but has minimal effect on the antioxidant/antinitrative protection of adiponectin. Circulation 119:835-44
Sharma, Kumar; Ramachandrarao, Satish; Qiu, Gang et al. (2008) Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest 118:1645-56
Xu, Shi-Qiong; Mahadev, Kalyankar; Wu, Xiangdong 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
Mahadev, Kalyankar; Wu, Xiangdong; Donnelly, Sylvia et al. (2008) Adiponectin inhibits vascular endothelial growth factor-induced migration of human coronary artery endothelial cells. Cardiovasc Res 78:376-84
Goldstein, Barry J; Scalia, Rosario (2007) Adipokines and vascular disease in diabetes. Curr Diab Rep 7:25-33
Ouedraogo, Raogo; Gong, Yulan; Berzins, Brett et al. (2007) Adiponectin deficiency increases leukocyte-endothelium interactions via upregulation of endothelial cell adhesion molecules in vivo. J Clin Invest 117:1718-26
Tao, Ling; Gao, Erhe; Jiao, Xiangying et al. (2007) Adiponectin cardioprotection after myocardial ischemia/reperfusion involves the reduction of oxidative/nitrative stress. Circulation 115:1408-16
Ouedraogo, Raogo; Wu, Xiangdong; Xu, Shi-Qiong 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 55:1840-6
Motoshima, Hiroyuki; Goldstein, Barry J; Igata, Motoyuki et al. (2006) AMPK and cell proliferation--AMPK as a therapeutic target for atherosclerosis and cancer. J Physiol 574:63-71
Ahmed, Intekhab; Goldstein, Barry J (2006) Cardiovascular risk in the spectrum of type 2 diabetes mellitus. Mt Sinai J Med 73:759-68