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


METHODS
Prospective, controlled, and randomized animal study.


METHODS
University laboratory.


METHODS
Male wild-type C57BL/6 mice and Ephx2 (-/-) mice.


METHODS
Male wild-type or Ephx2 (-/-) mice were subjected to transverse aorta constriction surgery.


RESULTS
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.


CONCLUSIONS
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.
1Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China. 2Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China. 3Department of Cardiology, Shenzhen Futian Hospital of Guangdong Medical College, Shenzhen, China. 4Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China. 5Department of Physiology, Georgia Regents University, Augusta, GA. 6Weil Institute of Critical Care Medicine, Rancho Mirage, CA.
Huanji
H
Zhang
Tong
T
Wang
Kun
K
Zhang
Yu
Y
Liu
Feifei
F
Huang
Xinhong
X
Zhu
Yang
Y
Liu
Mong-Heng
MH
Wang
Wanchun
W
Tang
Jingfeng
J
Wang
Hui
H
Huang
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D014662:Vasoconstrictor Agents; D016222:Fibroblast Growth Factor 2; D000804:Angiotensin II; D004851:Epoxide Hydrolases