This proposal represents a bench-to-bedside study to translate our recent findings in small animal models into the clinic. Cardiac remodeling is the heart?s prevailing response to extrinsic and intrinsic stimuli including pressure or volume overload, mutations of sarcomeric proteins, or loss of contractile mass from myocardial infarction (MI). Adverse cardiac remodeling is driven at the cellular level by myocyte hypertrophy, apoptosis, microvascular dysfunction, fibrosis, and electrical perturbations. Our group was the first to demonstrate beneficial effects of a novel class of soluble epoxide hydrolase (sEH) inhibitors in clinically relevant models of cardiac hypertrophy and failure. SEH is a critical enzyme in the cytochrome P450 pathway. Treatment with sEH inhibitors (sEHIs) results in the prevention of ventricular myocyte hypertrophy and electrical remodeling in pressure overload and myocardial infarction models. Our findings further demonstrate that treatment with sEHIs prevents cardiac fibroblast proliferation and fibrosis. This project is focused on the novel concept that pro-inflammatory metabolites of the cytochrome P450 pathway can result in adverse cardiac remodeling by increasing cardiac myocyte hypertrophy, apoptosis, coupled with a persistent increase in cytokines and chemokines leading to an increase in cardiac fibrosis. Hence, the main objective of this proposal is to use novel metabolomic profiling to determine the mechanistic roles of lipid mediators in adverse cardiac remodeling in patients post MI. New treatment paradigms for adverse cardiac remodeling are likely to be highly impactful.

Public Health Relevance

Cardiovascular disease is the leading cause of morbidity and mortality in the veteran patients and causes more deaths than all cancers combined. Hence, new treatment paradigms to target progressive adverse cardiac remodeling are likely to be of high impact clinically.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01CX001490-02
Application #
9454164
Study Section
Cardiovascular Studies A (CARA)
Project Start
2017-04-01
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
VA Northern California Health Care System
Department
Type
DUNS #
127349889
City
Mather
State
CA
Country
United States
Zip Code
95655
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