交感中枢RVLM去乙酰化酶Sirtuin1介导的自噬机制在中枢抗高血压效应中的作用研究

Hypertension is a globally prevalent disease, which causes serious complications such as stroke and heart attack. Rostral ventrolateral medulla (RVLM) is located in the brain stem, and controls sympathetic nerve outflow. Presympathetic neurons in the RVLM regulate sympathetic activity and blood pressure. Dysfunction of presympathetic neurons is closely related to hypertension. Sirtuin1 (Sirt1), known as NAD-dependent deacetylase, is a protein that in humans is encoded by the SIRT1 gene. Sirt1 is an enzyme that deacetylates proteins that contribute to cellular regulation (reaction to stressors, longevity). Sirt1 plays a protective role in multiple organ systems via reducing intracellular reactive oxygen species (ROS) and other mechanisms. Our previous study found that, Sirt1 expression in RVLM of spontaneously hypertensive rats (SHR) was decreased compared with normotensive WKY rats, and raised blood pressure of SHR can be reduced by Sirt1, which together suggests that Sirt1 plays an important role in the central regulation of blood pressure. Autophagy is the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components through the actions of lysosomes. The breakdown of cellular components promotes cellular survival during starvation by maintaining cellular energy levels. Autophagy allows the degradation and recycling of cellular components. A specific type of autophagy is called mitophagy, which is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. Hence mitophagy in neurons can reduce ROS and maintain normal neural activity..Several studies found that autophagy in RVLM neurons of SHR is lower than that of WKY rats, and Sirt1 can raise the level of autophagy in neurons. In conclusion,the hypothesis of this study is that deacetylase Sirtuin1 in RVLM plays an anti-hypertensive role via increasing the autophagy in presympathetic neurons. Our research will reveal new mechanisms of central blood pressure regulation, providing new drug targets for the prevention and treatment of essential hypertension.

交感神经活动亢进是高血压形成和发展的主要机制，头端延髓腹外侧区RVLM是调节交感活动和血压的关键中枢。RVLM活性氧族ROS增多是导致高血压的重要原因。去乙酰化酶Sirtuin1通过调控目的基因转录及靶蛋白活性降低细胞ROS，但其在高血压中枢心血管调控中的作用意义并不清楚。自噬是维持细胞自稳态的分解代谢现象，线粒体等自噬异常与氧化应激相关，并影响中枢神经元的兴奋性。前期预实验发现，高血压大鼠RVLM内Sirtuin1及自噬水平明显降低，上调Sirtuin1具有改善高血压的作用。因此本项目研究假设是RVLM去乙酰化酶Sirtuin1通过降低神经元的自噬导致抗氧化应激和抗高血压的作用，我们将明确Sirtuin1与自噬对血压的调节效应及两者间相互影响与作用机制。本课题将阐明Sirtuin1在心血管活动中枢调控中的作用和意义，并为探索高血压的防治新策略提供新的理论依据。