TyrRS-PARP1-Sirt3途径在白藜芦醇调控线粒体自噬抑制血管内皮细胞氧化应激损伤的作用研究

Researches indicated resveratrol (RSV) processes preventive and therapeutic effect on the oxidative stress injury on vascular endothelium which is the key step of atherosclerosis (AS). However, the underlying mechanism is still unknown. The oxidative stress injury can be alleviated by mitophagy. Our preliminary study has shown the RSV regulated the homeostasis of reactive oxygen species and inhibited the injury on endothelial cells through the Sirt3 signaling pathway. This project propose a hypothesis that “RSV could regulate the mitophagy through the TyrRS-PARP1-Sirt3 signaling pathway and consequently inhibit the oxidative stress injury on the endothelial cells”. We plan to verify the hypothesis in vitro and in vivo respectively. Firstly, we plan to clarify the function of mitophagy in the process that RSV inhibit the oxidative stress injury and the signaling pathway in the process that RSV regulates mitophagy in the primary endothelial cells. Secondly, we plan to verify the hypothesis in Sirt3 -/- rats that RSV could regulate the mitophagy through the TyrRS-PARP1-Sirt3 signaling pathway, inhibit the oxidative stress injury on the endothelial cells and then prevent the AS. The project is important in clarified the exact mechanism of the event that RSV inhibit the oxidative stress injury on the endothelial cells and providing scientific evidence on the researches of the AS intervention based on the pathway which Sirt3 regulate mitophagy.

白藜芦醇(RSV)对动脉粥样硬化(AS)关键环节—血管内皮氧化应激损伤有显著防治作用，但其作用机制尚未完全阐明。线粒体自噬可减轻氧化应激损伤，且申请人前期研究发现RSV可通过Sirt3信号途径调节线粒体活性氧稳态抑制内皮损伤。同时，最新研究揭示RSV的作用靶点是酪氨酰tRNA合成酶(TyrRS)。据此，本项目提出“RSV通过TyrRS-PARP1-Sirt3信号通路调控线粒体自噬，进而抑制血管内皮氧化应激损伤”的假说，拟通过基于原代细胞和基因敲除小鼠的研究，阐明线粒体自噬在RSV抑制血管内皮氧化应激损伤中的作用，并进一步明确TyrRS-PARP1-Sirt3信号通路调控线粒体自噬抑制血管内皮氧化应激损伤，进而防止AS的作用。本研究对阐明RSV抑制血管内皮氧化应激损伤的确切作用机制具有重要理论意义，并为基于Sirt3调控线粒体自噬途径防治AS的干预措施研究提供了科学依据。

白藜芦醇(RSV)对动脉粥样硬化(AS)关键环节—血管内皮氧化应激损伤有显著防治作用，但其作用机制尚未完全阐明。细胞自噬及线粒体融合过程与细胞氧化水平调控密切相关。同时，最新研究揭示酪氨酰tRNA合成酶(TyrRS)可能是RSV作用靶点，以及重要转录因子EB（TFEB）在自噬调控中有重要作用。据此，按原计划，本项目第一部分研究提出“RSV通过TyrRS-PARP1信号通路调控线粒体融合，进而抑制血管内皮氧化应激损伤”的假说，拟通过原代细胞研究阐明RSV通过激活TyrRS-PARP1信号通路，上调线粒体融合水平，抑制血管内皮氧化应激损伤。新增内容作为本项目第二部分研究，提出“RSV通过TFEB信号通路激活自噬，进而抑制血管内皮氧化应激损伤”的假说，拟通过原代细胞研究阐明RSV通过上调TFEB的蛋白表达和核转位活化水平，激活细胞自噬，进而抑制血管内皮氧化应激损伤。综上，本研究揭示了RSV抑制血管内皮氧化应激损伤的新作用机制，并为基于TyrRS以及TFEB信号途径防治AS的干预措施研究提供了科学依据。