Deletion of soluble epoxide hydrolase attenuates cardiac hypertrophy via down-regulation of cardiac fibroblasts-derived fibroblast growth factor-2

• Published in: Critical care medicine Vol. 42; no. 5; p. e345
• Main Authors: Zhang, Huanji, Wang, Tong, Zhang, Kun, Liu, Yu, Huang, Feifei, Zhu, Xinhong, Liu, Yang, Wang, Mong-Heng, Tang, Wanchun, Wang, Jingfeng, Huang, Hui
• Format: Journal Article
• Language: English
• Published: United States 01.05.2014
• Subjects: Angiotensin II - pharmacology; Animals; Cardiomegaly - chemically induced; Cardiomegaly - genetics; Cardiomegaly - metabolism; Disease Models, Animal; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Epoxide Hydrolases - antagonists & inhibitors; Epoxide Hydrolases - genetics; Epoxide Hydrolases - metabolism; Fibroblast Growth Factor 2 - blood; Fibroblast Growth Factor 2 - genetics; Fibroblast Growth Factor 2 - metabolism; Fibroblasts - metabolism; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Confocal; Myocardium - metabolism; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Prospective Studies; Real-Time Polymerase Chain Reaction; Vasoconstrictor Agents - pharmacology
• ISSN: 1530-0293
• DOI: 10.1097/CCM.0000000000000226

Inhibition of soluble epoxide hydrolase (Ephx2) has been shown to play a protective role in cardiac hypertrophy, but the mechanism is not fully understood. We tested the hypothesis that deletion of soluble epoxide hydrolase attenuates cardiac hypertrophy via down-regulation of cardiac fibroblasts-derived fibroblast growth factor-2. Prospective, controlled, and randomized animal study. University laboratory. Male wild-type C57BL/6 mice and Ephx2 (-/-) mice. Male wild-type or Ephx2 (-/-) mice were subjected to transverse aorta constriction surgery. Four weeks after transverse aorta constriction, Ephx2 (-/-) mice did not develop significant cardiac hypertrophy as that of wild-type mice, indicated by no changes in the ratio of heart weight/body weight and ventricular wall thickness after transverse aorta constriction. Cardiac fibroblast growth factor-2 increased in wild-type-transverse aorta constriction group but this did not change in Ephx2 (-/-)-transverse aorta constriction group, and the serum level of fibroblast growth factor-2 did not change in both groups. In vitro, cardiac fibroblasts were stimulated by angiotensin II to analyze the expression of fibroblast growth factor-2. The effect of increased fibroblast growth factor-2 from cardiac fibroblasts induced by angiotensin II was attenuated by soluble epoxide hydrolase deletion. ERK1/2, p38, and AKT kinase were involved in fibroblast growth factor-2 expression regulated by angiotensin II, and soluble epoxide hydrolase deletion lowered the phosphorylation of ERK1/2 not p38 or AKT to mediate fibroblast growth factor-2 expression. In addition, soluble epoxide hydrolase deletion did not attenuate cardiomyocytes hypertrophy induced by exogenous fibroblast growth factor-2. Our present data demonstrated that deletion of soluble epoxide hydrolase prevented cardiac hypertrophy not only directly to cardiomyocytes but also to cardiac fibroblasts by reducing expression of fibroblast growth factor-2.