Deletion of Soluble Epoxide Hydrolase Attenuates Cardiac Hypertrophy via Down-Regulation of Cardiac Fibroblasts-Derived Fibroblast Growth Factor-2
Deletion of Soluble Epoxide Hydrolase Attenuates Cardiac Hypertrophy via Down-Regulation of Cardiac Fibroblasts-Derived Fibroblast Growth Factor-2
复制标题
删除可溶性环氧化物水解酶可通过下调心脏成纤维细胞衍生的成纤维细胞生长因子 2 来减轻心脏肥大
DOI：
10.1097/ccm.0000000000000226
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发表时间：
2014
影响因子：
8.8
通讯作者：
Huang Hui
中科院分区：
文献类型：
--
作者：
Zhang Huanji;Wang Tong;Zhang Kun;Liu Yu;Huang Feifei;Zhu Xinhong;Liu Yang;Wang Mong-Heng;Tang Wanchun;Wang Jingfeng;Huang Hui
目的：抑制可溶性环氧化物水解酶（Ephx 2）已被证明在心肌肥厚中发挥保护作用，但其机制尚未完全了解。我们测试了可溶性环氧化物水解酶的缺失通过下调心脏成纤维细胞衍生的成纤维细胞生长因子-2来减弱心脏肥大的假设。设计：前瞻性、对照和随机动物研究。设置：大学实验室。受试者：雄性野生型C57 BL/6小鼠和Ephx 2（-/-）小鼠。干预：雄性野生型或Ephx 2（-/-）小鼠接受横向主动脉缩窄手术。测量和主要结果：在横向主动脉缩窄后四周，Ephx 2（-/-）小鼠没有发展出与野生型小鼠相同的显著心脏肥大，表明在横主动脉缩窄后心脏重量/体重比值和心室壁厚度没有变化。心脏成纤维细胞生长因子-2在野生型-横主动脉缩窄组中增加，但在Ephx 2（-/-）-横主动脉缩窄组中没有改变，并且两组中成纤维细胞生长因子-2的血清水平没有改变。在体外，用血管紧张素II刺激心脏成纤维细胞，分析成纤维细胞生长因子-2的表达。血管紧张素II诱导的心脏成纤维细胞的成纤维细胞生长因子-2增加的效果被可溶性环氧化物水解酶删除减弱。ERK 1/2、p38和AKT激酶参与血管紧张素II调节的成纤维细胞生长因子2表达，可溶性环氧化物水解酶缺失降低了ERK 1/2的磷酸化，而不是p38或AKT介导的成纤维细胞生长因子2表达。此外，可溶性环氧化物水解酶的缺失并不能减轻外源性成纤维细胞生长因子-2诱导的心肌细胞肥大。结论：可溶性环氧化物水解酶的缺失不仅可以直接抑制心肌细胞肥大，而且可以通过降低成纤维细胞生长因子-2的表达来抑制心肌成纤维细胞肥大。
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.