期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 14, 页码 5618-5623出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1221972110
关键词
epoxyeicosatrienoic acids; dihydroxyeicosatrienoic acids; thymocyte differentiation antigen; Cluster of Differentiation 90; fibroblast specific protein 1
资金
- National Institutes of Health (NIH) [HL85727, HL85844]
- Veterans Administration Merit Review Grant [I01 BX000576]
- Howard Hughes Medical Institute Med-into-Grad Training Program to University of California Davis (UCD)
- American Heart Association (AHA) Western States Affiliate Predoctoral Fellowship Award
- NIH T32 Training Grant in Basic and Translational Cardiovascular Science [T32 HL86350]
- Sarnoff Cardiovascular Research Foundation
- AHA Western States Affiliate Beginning Grant-in-Aid
- Harold Amos Medical Faculty Development Award from Robert Wood Johnson Foundation
- National Institute of Environmental Health Sciences (NIEHS) [R37 ES02710]
- NIEHS Superfund Basic Research Program [P42 ES04699]
- NIEHS Center for Children's Environmental Health and Disease Prevention [P01 ES11269]
- UCD Health System
- American Asthma Society
Tissue fibrosis represents one of the largest groups of diseases for which there are very few effective therapies. In the heart, myocardial infarction (MI) resulting in the loss of cardiac myocytes can culminate in adverse cardiac remodeling leading to eventual heart failure. Adverse cardiac remodeling includes myocyte hypertrophy, fibrosis, and electrical remodeling. We have previously demonstrated the beneficial effects of several potent soluble epoxide hydrolase inhibitors (sEHIs) in different models of cardiac hypertrophy and failure. Here, we directly determine the molecular mechanisms underlying the beneficial effects of sEHIs in cardiac remodeling post-MI. Treatment with a potent sEHI, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl) urea (TPPU), which was started 1 wk post-MI in a murine model, results in a significant improvement in cardiac function. Importantly, treatment with TPPU results in a decrease in cardiac fibrosis as quantified using histological and immunostaining techniques. Moreover, single-cell-based assays demonstrate that treatment with TPPU results in a significant decrease not only in the percentages but also the proliferative capacity of different populations of cardiac fibroblasts as well as a reduction in the migration of fibroblasts into the heart from the bone marrow. Our study provides evidence for a possible unique therapeutic strategy to reduce cardiac fibrosis and improve cardiac function post-MI.
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