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 #
5R01HL131006-05
Application #
9614306
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
2019-01-01
Budget End
2019-12-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Maruyama, Sonomi; Wu, Chia-Ling; Yoshida, Sumiko et al. (2018) Relaxin Family Member Insulin-Like Peptide 6 Ameliorates Cardiac Fibrosis and Prevents Cardiac Remodeling in Murine Heart Failure Models. J Am Heart Assoc 7:
Sano, Soichi; Oshima, Kosei; Wang, Ying et al. (2018) Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1?/NLRP3 Inflammasome. J Am Coll Cardiol 71:875-886
Seki, Mitsuru; Powers, Jeffery C; Maruyama, Sonomi et al. (2018) Acute and Chronic Increases of Circulating FSTL1 Normalize Energy Substrate Metabolism in Pacing-Induced Heart Failure. Circ Heart Fail 11:e004486
Sano, Soichi; Wang, Ying; Walsh, Kenneth (2018) Clonal Hematopoiesis and Its Impact on Cardiovascular Disease. Circ J 83:2-11
Fuster, José J; Walsh, Kenneth (2018) Somatic Mutations and Clonal Hematopoiesis: Unexpected Potential New Drivers of Age-Related Cardiovascular Disease. Circ Res 122:523-532
Sano, Soichi; Oshima, Kosei; Wang, Ying et al. (2018) CRISPR-Mediated Gene Editing to Assess the Roles of Tet2 and Dnmt3a in Clonal Hematopoiesis and Cardiovascular Disease. Circ Res 123:335-341
Zuriaga, María A; Fuster, José J; Farb, Melissa G et al. (2017) Activation of non-canonical WNT signaling in human visceral adipose tissue contributes to local and systemic inflammation. Sci Rep 7:17326
Wu, Chia-Ling; Satomi, Yoshinori; Walsh, Kenneth (2017) RNA-seq and metabolomic analyses of Akt1-mediated muscle growth reveals regulation of regenerative pathways and changes in the muscle secretome. BMC Genomics 18:181
Karki, Shakun; Ngo, Doan T M; Farb, Melissa G et al. (2017) WNT5A regulates adipose tissue angiogenesis via antiangiogenic VEGF-A165b in obese humans. Am J Physiol Heart Circ Physiol 313:H200-H206
Fuster, José J; MacLauchlan, Susan; Zuriaga, María A et al. (2017) Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355:842-847

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