缺血再灌注心肌损伤的新机制探索：内质网应激、sEH活化、与TRPC通道在冠脉功能损伤中的关联和信号传导

Compromised coronary blood flow resulting from coronary endothelial dysfunction contributes to myocardial ischemia-reperfusion (I-R) injury. It remains incompletely understood how I-R impairs coronary endothelial function and there are lack of studies regarding the linkage among different mechanisms. Endoplasmic reticulum (ER) stress and activation of soluble epoxide hydrolase (sEH) have been implicated in vascular endothelial dysfunction in many diseases, however, whether these two mechanisms interact during I-R to compromise coronary endothelial function remains unknown. Being based on our recent findings, this study will first investigate the role of ER stress in sEH activation during I-R with exploration of the signaling pathways involved. Further, we will study the effect of such signal transduction on endothelial TRPC3 channels to reveal the molecular basis of I-R-induced TRPC3 inhibition, which was previously reported by our group. Through studying for the first time the linkage among ER stress, sEH, and TRPC channels, the present study will advance our mechanistic understanding of I-R-induced endothelial dysfunction, which may help identify new potential target sites and promote the development of strategies against I-R for myocardial protection.

冠状动脉内皮功能障碍引起的冠脉血流受损参与缺血再灌注（I-R）引起的心肌损伤。目前对I-R损伤冠脉内皮功能的机制理解仍不完全，对各机制之间的相互关联的认知则更为缺乏。内质网应激或sEH活化/EETs下调与多种疾病的血管内皮功能障碍有关，然而此两种机制是否相互关联参与I-R冠脉内皮损伤未有研究。本项目将在我们近年来一系列工作的基础上，首先对I-R时内质网应激调控内皮sEH表达的信号通路做出探讨，进而研究该信号传导对于TRPC3通道的调控作用，以明确我们之前发现的I-R抑制内皮TRPC3通道的分子基础。本研究通过首次对内质网应激、sEH活化/EETs下调、与TRPC通道之间的相互关联及信号传导的探讨，进一步深入对I-R损伤内皮功能的分子机制的理解，为发展心肌I-R损伤的防治策略提供新的思路。

如何有效对抗缺血再灌注损伤仍然是缺血性心脏病内科及外科治疗所面临的挑战。内皮细胞功能障碍引起的冠脉血流受损在缺血再灌注心肌损伤中起着十分重要的作用。目前对缺血再灌注损伤的机制理解仍不完全，对各机制之间的相互关联的认知则更为缺乏。已知内质网应激和可溶性环氧化物水解酶（sEH）活化参与多种心血管病变包括缺血再灌注的损伤进程，然而此两种机制是否相互关联参与缺血再灌注引起的冠脉和心肌功能损伤尚未有研究。我们既往还曾报道缺血再灌注可通过抑制TRPC3通道向细胞膜表面转运引起冠脉内皮舒张功能障碍。本项目首次对内质网应激、生物酶（sEH）、与离子通道（TRPC3）这三者在缺血再灌注损伤中的关联作用做出探讨。研究发现内质网应激信号臂分子IRE1α激活促进了JNK磷酸化，进而通过调控c-Jun/AP-1促进sEH的转录，由此引起的sEH表达上调和活化介导了缺血再灌注后的冠脉内皮舒张功能损伤和心肌收缩功能减弱。sEH对TRPC3通道的表达和电流强度具有调控作用，该调控由11,12-EET介导。通过首次建立IRE1-JNK-c-Jun/AP-1-sEH传导通路及11,12-EET-TRPC3-Ca2+信号调控机制，本研究深入了对缺血再灌注损伤分子机制的理解，为发展心肌缺血再灌注损伤的防治策略提供了新的思路。