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

Huanji Zhang, Tong Wang, Kun Zhang, Yu Liu, Feifei Huang, Xinhong Zhu, Yang Liu, Mong-Heng Wang, Wanchun Tang, Jingfeng Wang, Hui Huang

Research output: Contribution to journalArticle

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Abstract

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. Design: Prospective, controlled, and randomized animal study. Setting: University laboratory. Subjects: Male wild-type C57BL/6 mice and Ephx2 (-/-) mice. Interventions: Male wild-type or Ephx2 (-/-) mice were subjected to transverse aorta constriction surgery. Measurements and Main 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.

Original languageEnglish (US)
JournalCritical Care Medicine
Volume42
Issue number5
DOIs
StatePublished - Jan 1 2014

Fingerprint

Epoxide Hydrolases
Cardiomegaly
Fibroblast Growth Factor 2
Down-Regulation
Fibroblasts
Constriction
Aorta
Angiotensin II
Cardiac Myocytes
Inbred C57BL Mouse
Hypertrophy
Phosphotransferases
Body Weight
Phosphorylation
Weights and Measures

Keywords

  • cardiac fibroblast
  • cardiac hypertrophy
  • fibroblast growth factor-2
  • soluble epoxide hydrolase

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Deletion of soluble epoxide hydrolase attenuates cardiac hypertrophy via down-regulation of cardiac fibroblasts-derived fibroblast growth factor-2. / Zhang, Huanji; Wang, Tong; Zhang, Kun; Liu, Yu; Huang, Feifei; Zhu, Xinhong; Liu, Yang; Wang, Mong-Heng; Tang, Wanchun; Wang, Jingfeng; Huang, Hui.

In: Critical Care Medicine, Vol. 42, No. 5, 01.01.2014.

Research output: Contribution to journalArticle

Zhang, Huanji ; Wang, Tong ; Zhang, Kun ; Liu, Yu ; Huang, Feifei ; Zhu, Xinhong ; Liu, Yang ; Wang, Mong-Heng ; Tang, Wanchun ; Wang, Jingfeng ; Huang, Hui. / Deletion of soluble epoxide hydrolase attenuates cardiac hypertrophy via down-regulation of cardiac fibroblasts-derived fibroblast growth factor-2. In: Critical Care Medicine. 2014 ; Vol. 42, No. 5.
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AU - Wang, Tong

AU - Zhang, Kun

AU - Liu, Yu

AU - Huang, Feifei

AU - Zhu, Xinhong

AU - Liu, Yang

AU - Wang, Mong-Heng

AU - Tang, Wanchun

AU - Wang, Jingfeng

AU - Huang, Hui

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AB - 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. Design: Prospective, controlled, and randomized animal study. Setting: University laboratory. Subjects: Male wild-type C57BL/6 mice and Ephx2 (-/-) mice. Interventions: Male wild-type or Ephx2 (-/-) mice were subjected to transverse aorta constriction surgery. Measurements and Main 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.

KW - cardiac fibroblast

KW - cardiac hypertrophy

KW - fibroblast growth factor-2

KW - soluble epoxide hydrolase

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