内源性二氧化硫对动脉粥样硬化胆固醇代谢的调节及SCAP-SREBP信号途径的作用研究

Atherosclerosis (AS) is an important pathological manifestation of many common cardiovascular diseases, but the mechanisms of the development of AS and cholesterol metabolism, one of the main causes of AS, are not completely understood yet. In recent years, sulfur dioxide (SO2) can be produced endogenously from the metabolism of the sulfur-containing amino acid as metabolic products, and is considered to be one of the new gasotransmitters regulating cardiovascular functions. There are important implications for us to invest the roles SO2 played in cholesterol metabolism. Using atherosclerotic rats and HepG2 cells loaded LDL as the objects, this study are designed to reveal the regulations of endogenous sulfur dioxide on the cholesterol metabolism in liver by making up a SO2 deficiency and overexpression or knockdown AAT genes; to clarify in which parts SO2 had an effect in cholesterol metabolism concerning HMGR, a key enzyme in cholesterol synthesis, and LDLR, a regulator of cholesterol degradation; to focus on SCAP-SREBP pathway, one of the main regulators of cholesterol homeostasis in liver and to reveal PI3K / Akt signal transduction pathway involved in the regulation of sulfur dioxide in cholesterol metabolism in liver. With the study above, it will be clarify the definite effects of SO2 on cholesterol metabolism and the possible mechanisms and signal transduction pathways involved. The findings might significantly improve our understanding of the mechanisms responsible for AS, and provide new ideas to prevent us from disorder of lipid metabolism, the main feature of AS -related diseases.

动脉粥样硬化是众多心血管疾病共同的病理基础，胆固醇代谢紊乱是主要病因之一，阐明其发病机制成为当今医学领域亟待解决的重大科学问题。近年来，内源性二氧化硫被认为是心血管功能调节的新型气体信号分子，研究其对胆固醇代谢调节具有重要意义。本研究将以动脉粥样硬化大鼠及LDL负荷HepG2细胞为研究对象，通过外源性补充二氧化硫衍生物及过表达或敲低AAT基因等方法，揭示内源性二氧化硫对动脉粥样硬化形成中肝脏胆固醇含量的调节作用；以胆固醇合成关键酶HMGR及降解调节因素LDLR为重点，揭示二氧化硫调节胆固醇代谢的作用环节；通过对胆固醇代谢调控因子SCAP-SREBP途径的研究，揭示其在二氧化硫调节胆固醇代谢的意义；阐明PI3K/Akt信号转导通路介导二氧化硫调节肝脏胆固醇代谢的过程。通过上述研究，深化动脉粥样硬化胆固醇代谢紊乱的发病机制理论，为防治以脂质代谢紊乱为主要特征的动脉粥样硬化相关疾病提供新的思路。