心肌肥厚是心功能逐渐恶化为心力衰竭的一个重要危险因素。国内外报道和我们前期研究均证实环氧二十碳三烯酸（EETs）具有抑制心肌肥厚的作用，然而具体机制目前尚不清楚。新近研究表明线粒体功能障碍在心肌肥厚过程中扮演关键角色。我们在体和离体的预实验结果均证实EETs能够降低线粒体膜电位的损失、稳定线粒体的双层膜结构，进而抑制机械应力诱导的线粒体损伤。此外，PGC-1α在线粒体能量代谢调控中至关重要。结合前期研究和预实验结果，我们提出EETs通过上调PGC-1α抑制机械应力所致线粒体损伤，进而抑制心肌肥厚的假说。本研究拟通过小鼠主动脉弓缩窄术构建心肌肥厚模型，同时采用机械应力刺激心肌细胞建立心肌细胞肥大模型，以sEH基因敲除上调EETs，在在体和离体水平探讨EETs对心肌肥厚的作用。本研究旨在深入剖析EETs—PGC-1α—线粒体能量代谢—心肌肥厚的作用规律，为心肌肥厚的防治提供新的方向和靶点。

Cardiac hypertrophy is considered to be a key process and critical factor for the progression of chronic heart failure. Both our preliminary studies and other reports demonstrated that EETs could attenuate cardiac hypertrophy, however the detail mechanism is still unclear. Recent studies demonstrated that mitochondrial dysfunction plays a critical role in the induction and manifestation of cardiac hypertrophy. And our preliminary results showed that EETs could limit mitochondrial dysfunction induced by mechanical stress through reducing the loss of mitochondrial membrane potential and stabilizing mitochondria membrane. Furthermore, PGC-1α is found to have association with mitochondrial energy metabolism. Based on our previous and preliminary results, we raise the hypothesis that EETs could attenuate mitochondrial dysfunction induced by mechanical stress through activating PGC-1α, and prevent cardiac hypertrophy. In this proposal, we will explore the effect of EETs on cardiac hypertrophy by using in vivo model of cardiac hypertrophy induced by transverse aorta constriction and in vitro model induced by mechanical stretch stimulation, and upregulation of EETs by sEH knock out and 14,15-EETs. The detail mechanism of EETs—PGC-1α—mitochondrial energy metabolism—cardiac hypertrophy will be deeply investigated. This project well provide a new therapeutic intervention for cardiac hypertrophy.