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. ? ? ?
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