Ischemic heart disease is the leading cause of morbidity and mortality in the United States. Obesity- linked diseases including type 2 diabetes largely contribute to the incidence, severity and outcome of ischemic heart disease. However, the link between obesity and the development of cardiovascular disease is poorly understood at a molecular level. Adipose tissues secrete adipokines that directly or indirectly affect obesity-linked disorders. Adiponectin is a circulating adipokine that is downregulated in patients with obesity-linked diseases including type 2 diabetes, the metabolic syndrome and ischemic heart disease. Studies with adiponectin-deficient mice show that adiponectin has important anti- atherogenic and anti-diabetic properties. Previously, we showed that adiponectin promotes angiogenic repair of ischemic hindlimbs. Recently, we also demonstrated that adiponectin protects against acute myocardial ischemia-reperfusion injury. These cardiac protective effects are mediated by the anti- apoptotic actions of AMP-activated kinase (AMPK) and the anti-inflammatory actions of cyclooxygenase- 2 (COX-2) in myocardial cells. In contrast to AMPK, the signaling mechanisms by which adiponectin activates the COX-2 pathway are unknown. In the proposed studies, we hypothesize that adiponectin accelerates angiogenic response to chronic myocardial ischemia and regulates cardiac remodeling after myocardial infarction. The proposed studies will also focus on the receptor-mediated signaling mechanisms that mediate the adiponectin-COX-2 and -AMPK regulatory axes. To achieve these objectives, we will:
Aim 1) Analyze whether adiponectin has beneficial effects on cardiac remodeling after myocardial infarction.
Aim 2) Analyze the role of adiponectin in EPC mobilization and function.
Aim 3) Analyze the adiponectin-COX-2 and -AMPK regulatory axes in vitro. Collectively, the proposed study will contribute to our understanding of the mechanisms that regulate cardiac remodeling and angiogenesis in association with obesity-linked disorders, and may provide insight for the development of novel approaches to treat ischemic cardiovascular disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Boston University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Nakamura, Kazuto; Fuster, José J; Walsh, Kenneth (2014) Adipokines: a link between obesity and cardiovascular disease. J Cardiol 63:250-9
Ouchi, Noriyuki; Parker, Jennifer L; Lugus, Jesse J et al. (2011) Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11:85-97
Shimano, Masayuki; Ouchi, Noriyuki; Shibata, Rei et al. (2010) Adiponectin deficiency exacerbates cardiac dysfunction following pressure overload through disruption of an AMPK-dependent angiogenic response. J Mol Cell Cardiol 49:210-20
Ouchi, Noriyuki; Higuchi, Akiko; Ohashi, Koji et al. (2010) Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity. Science 329:454-7
Higuchi, Akiko; Ohashi, Koji; Shibata, Rei et al. (2010) Thiazolidinediones reduce pathological neovascularization in ischemic retina via an adiponectin-dependent mechanism. Arterioscler Thromb Vasc Biol 30:46-53
Oshima, Yuichi; Ouchi, Noriyuki; Shimano, Masayuki et al. (2009) Activin A and follistatin-like 3 determine the susceptibility of heart to ischemic injury. Circulation 120:1606-15
Higuchi, Akiko; Ohashi, Koji; Kihara, Shinji et al. (2009) Adiponectin suppresses pathological microvessel formation in retina through modulation of tumor necrosis factor-alpha expression. Circ Res 104:1058-65
Kondo, Megumi; Shibata, Rei; Miura, Rie et al. (2009) Caloric restriction stimulates revascularization in response to ischemia via adiponectin-mediated activation of endothelial nitric-oxide synthase. J Biol Chem 284:1718-24
Ohashi, Koji; Ouchi, Noriyuki; Sato, Kaori et al. (2009) Adiponectin promotes revascularization of ischemic muscle through a cyclooxygenase 2-dependent mechanism. Mol Cell Biol 29:3487-99
Ikeda, Yasumasa; Ohashi, Koji; Shibata, Rei et al. (2008) Cyclooxygenase-2 induction by adiponectin is regulated by a sphingosine kinase-1 dependent mechanism in cardiac myocytes. FEBS Lett 582:1147-50

Showing the most recent 10 out of 20 publications