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

Padmini Sirish, Ning Li, Jun Yan Liu, Kin Sing Stephen Lee, Sung Hee Hwang, Hong Qiu, Cuifen Zhao, Siu Mei Ma, Javier E Lopez, Bruce D. Hammock, Nipavan Chiamvimonvat

Research output: Contribution to journalArticle

52 Scopus citations

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. Wehave 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 themolecular 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), whichwas 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.

Original languageEnglish (US)
Pages (from-to)5618-5623
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number14
DOIs
StatePublished - Apr 2 2013

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Keywords

  • Cluster of Differentiation 91
  • Dihydroxyeicosatrienoic acids
  • Epoxyeicosatrienoic acids
  • Fibroblast specific protein 1
  • Thymocyte differentiation antigen

ASJC Scopus subject areas

  • General

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