Obesity is the major worldwide epidemic of the 21st century. Cardiovascular disease (CVD) is the predominant cause of mortality in obese individuals. However, the mechanisms that link adipose tissue dysfunction to CVD remain incompletely understood. A growing body of evidence shows that adipose tissue secretes bioactive molecules called adipokines, and that obesity contributes to CVD due to unbalanced adipokine secretion, creating a chronic low-grade inflammatory state. Notably, we and others have shown that experimental manipulations of adipokine levels can have marked effects on cardiovascular disease processes in mouse genetic models fed a normal chow diet, documenting that changes in adipokine levels are sufficient to confer changes in cardiovascular function independent of its confounding metabolic actions. Our laboratory has identified Sfrp5 as a new anti-inflammatory adipokine, which antagonizes the pro-inflammatory activity of Wnt5a, a regulator of non-canonical Wnt signaling. While these studies showed that the Sfrp5/Wnt5a axis modulates inflammation in the microenvironment of adipose tissue and the peripheral vascular compartment, its actions in the heart remain unexplored. Here, we propose to investigate the role of the non-canonical Wnt5a regulatory system in the development post-myocardial infarction (post-MI) remodeling. We hypothesize that the aberrant regulation of Sfrp5/Wnt5a in the obese state is a highly significant, but previously unrecognized, mechanism by which metabolic dysfunction promotes ischemic heart disease.

Public Health Relevance

Cardiovascular disease is the predominant cause of mortality in obese individuals; however, the mechanisms that link adipose tissue dysfunction to cardiovascular disease remain incompletely understood. A growing body of evidence shows that adipose tissue secretes bioactive molecules called adipokines, and that obesity contributes to cardiovascular disease due to unbalanced adipokine secretion. Here, we propose to investigate the roles of these molecules in the development post-myocardial infarction remodeling.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL131006-01
Application #
9034132
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
2016-01-01
Project End
2019-12-31
Budget Start
2016-01-01
Budget End
2016-12-31
Support Year
1
Fiscal Year
2016
Total Cost
$529,512
Indirect Cost
$206,704
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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