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Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5618-23. doi: 10.1073/pnas.1221972110. Epub 2013 Mar 14.

Unique mechanistic insights into the beneficial effects of soluble epoxide hydrolase inhibitors in the prevention of cardiac fibrosis.

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1
Division of Cardiovascular Medicine, University of California, Davis, CA 95616, USA.

Abstract

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.

PMID:
23493561
PMCID:
PMC3619365
DOI:
10.1073/pnas.1221972110
[Indexed for MEDLINE]
Free PMC Article
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