TFEB通过改善线粒体功能保护血管内皮抗动脉粥样硬化的作用及机制研究

Cardiovascular diseases (CVDs) caused by atherosclerosis (AS) are the major killers that threatening human health. Endothelial cell (EC) damage is one of the initiating factors of AS. At present, surgeries and medicines are the conventional treatments of AS, however, with some problems such as restenosis and side effects, which can’t prevent the pathogenesis of AS. Therefore, there is no effective treatment for AS. Studies have suggested that transcription factor EB (TFEB) can upregulate autophagy and promote PGC-1α transcription to increase mitochondrial biogenesis. While whether TFEB-PGC-1α axis protecting EC against AS has not been reported. Here, our preliminary results showed that TFEB can decrease plaque size, alleviate high-fat-induced EC dysfunction, apoptosis and mitochondrial damage, meanwhile, increase mitochondrial autophagy and biogenesis. Based on these theories, we hypothesize that TFEB can delay AS by protecting endothelia via improving mitochondrial function. In this study, we aim to elucidate the mechanism underlying the protection effects of TFEB during AS by establishing TFEB, autophagy and PGC-1α gene knockout mice and cell models, respectively. The present study is to explore whether TFEB can promote the clearance of damaged mitochondria through mitochondrial autophagy, as well as enhance PGC-1α transcription to promote mitochondrial biogenesis, thereby preventing EC mitochondrial damage from high fat, consequently, which alleviates the levels of oxidative stress and inflammation to delay the progression of AS. This study can reveal the novel role of TFEB in the pathogenesis of AS and provide a theoretical basis for its clinical application.

动脉粥样硬化（AS）性心血管疾病是威胁人类健康的头号杀手，而血管内皮（EC）损伤是其始动因素。目前AS的治疗方法包括手术和药物治疗，但存在血管再狭窄和副作用强等问题，且不能从源头上阻断病情进展，尚缺乏有效治疗措施。文献表明转录因子EB（TFEB）可上调自噬并促进PGC-1α转录调控线粒体合成，而这一通路能否保护血管内皮抗AS目前尚无报道。预实验显示，TFEB能缩小AS斑块，减轻高脂引起的EC功能损伤和凋亡，增加线粒体自噬与合成。由此提出假说：TFEB可能通过增加线粒体自噬与合成保护血管内皮抗AS。本项目拟构建TFEB、自噬和PGC-1α相关基因敲除小鼠与细胞模型，探讨TFEB是否通过上调自噬促受损线粒体清除，增强PGC-1α转录促线粒体合成，改善高脂引起的EC线粒体损伤，降低炎症和氧化应激水平，最终延缓AS进展。本研究可揭示TFEB在AS发生过程中的新型作用并为其临床转化提供理论基础。

心血管疾病（Cardiovascular disease, CVD）是目前全球威胁人类健康最严重的疾病，动脉粥样硬化（Atherosclerosis, AS）是导致急性心肌梗死和心衰等严重CVD的主要原因，且患病率、死亡率仍处于上升阶段。因此，动脉粥样硬化性心血管疾病已成为中国乃至全世界范围内一个亟待解决的公共卫生问题。虽然临床上针对AS治疗方法主要包括药物治疗和手术治疗，但药物发挥作用缓慢，手术创伤较大，存在一定的风险，且易导致严重的并发症等。故目前针对AS治疗尚缺乏有效手段，寻求一种针对AS病因且无创的治疗方法迫在眉睫。内皮功能紊乱是动脉粥样硬化性心血管疾病发生的始动因素，针对内皮功能紊乱的发生机制，寻求增强内皮防御能力的防治手段是目前动脉粥样硬化的研究热点。转录因子EB（TFEB）是近年来发现的自噬-溶酶体通路的重要调节因子，通过细胞核转位促进溶酶体合成和自噬活化，调节细胞自噬、细胞器的生物合成和脂质代谢等过程，可作为多种与自噬或溶酶体功能紊乱相关疾病的治疗靶点，具有重要的治疗意义。而TFEB对内皮的调控作用及其与AS病情进展的关系尚不明确。本研究发现，TFEB可以有效抑制ox-LDL引起的内皮细胞损伤，包括炎症因子的表达、单核细胞的粘附及内皮连接的完整性。机制上我们发现，TFEB可以增强Draxin的转录和蛋白表达从而抑制Wnt/β-catenin信号通路，进而抑制内皮间质转化过程，有效抑制EC炎症，从而延缓AS进展。本研究结果可开拓以TFEB为靶点的AS治疗方法，为开发以TFEB为靶点的AS治疗药物提供理论支持。