Obesity, is epidemic in the United States and is emerging as a strong independent risk factor for complications of atherosclerotic vascular disease such as myocardial infarction and stroke. Since thrombosis overlying an atherosclerotic plaque is the immediate cause of myocardial infarction and stroke, the obese state may promote the development of thrombosis at sites of vascular disease. Leptin, a hormone produced by the adipocyte, increases with obesity and may be one of the mediators responsible for the increased cardiovascular risk associated with obesity. We have recently demonstrated that leptin or leptin receptor deficiency is protective against thrombosis in a mouse model of arterial injury. Furthermore, this protective effect of leptin deficiency on thrombosis is reversed with leptin replacement. Consistent with a prothrombotic effect of leptin in humans, a recent clinical trial has demonstrated that elevated plasma leptin is an independent risk factor for cardiovascular events. The goals of this proposal are to characterize the impact of varying elevations of ieptin on thrombosis and atherosclerosis using established mouse models. In addition, mice with plateiet and endothelial leptin receptor deficiency will be generated using the Cre-loxP system to determine the relevant target tissues involved in mediating the adverse vascular effects of leptin. These studies will determine the functional in vivo significance of leptin and various leptin receptor pools in vascular disease and have important implications for understanding the effects of obesity on cardiovascular complications.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073150-04
Application #
7031017
Study Section
Special Emphasis Panel (ZHL1-CSR-S (F1))
Program Officer
Link, Rebecca P
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$353,717
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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