Journal
CRITICAL CARE MEDICINE
Volume 42, Issue 5, Pages E345-E354Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CCM.0000000000000226
Keywords
soluble epoxide hydrolase; cardiac fibroblast; fibroblast growth factor-2; cardiac hypertrophy
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Funding
- National Natural Science Foundation of China (NSFC) [81070125, 81270213]
- American Heart Association (AHA) [AHASE0054]
- NSFC [81270212, 81170647, 91029742, 81370837, 30973207]
- Fok Ying-Tong Education Foundation for Young Teachers in the Higher Education Institutions of China [132030]
- Yat-Sen Scholarship for Young Scientists
- Science and Technology star of Zhujiang (Guangzhou)
- Guangdong Province Key Laboratory of Computational Science at the Sun Yat-Sen University
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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.
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