title: Unique mechanistic insights into the beneficial effects of soluble epoxide hydrolase inhibitors in the prevention of cardiac fibrosis.
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.
authors.affiliation: Division of Cardiovascular Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Padmini
authors.initials: P
authors.lastname: Sirish
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Jun-Yan
authors.initials: JY
authors.lastname: Liu
authors.forename: Kin Sing Stephen
authors.initials: KS
authors.lastname: Lee
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.forename: Hong
authors.initials: H
authors.lastname: Qiu
authors.forename: Cuifen
authors.initials: C
authors.lastname: Zhao
authors.forename: Siu Mei
authors.initials: SM
authors.lastname: Ma
authors.forename: Javier E
authors.initials: JE
authors.lastname: López
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Nipavan
authors.initials: N
authors.lastname: Chiamvimonvat
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D004452:Echocardiography; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D005355:Fibrosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D005434:Flow Cytometry; D051379:Mice; D009203:Myocardial Infarction / Q000150:complications*; D054883:Oxylipins / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: C581572:1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea; D016207:Cytokines; D054883:Oxylipins; D010671:Phenylurea Compounds; D010880:Piperidines; D004851:Epoxide Hydrolases