CYP2E1对心脏酮体利用及能量代谢的机制研究

CYP2E1 is involved in the metabolism of a vast array of endogenous substrates and drugs. The expression level of CYP2E1 increases significantly under ischemia, dilated cardiomyopathy (DCM) and hypertension. In our previous studies, CYP2E1 overexpression exacerbates the DCM development through oxidative stress and apoptosis, while knockdown of CYP2E1 can prevent this proceeding. Why the expression of CYP2E1 increased in heart diseases, and it must be very important in the development of the body, and the real function of CYP2E1 on heart was still not clear. The level and catabolism of acetone increase in heart failure and hypoxia associated heart diseases, and ketone bodies can induce the activity of CYP2E1. So we hypothesised that CYP2E1 involved the myocardial energy supply by inducing ketone bodies catabolism. In the present study, we will use heart tissue specific CYP2E1 overexpression and knockdown transgenic mice, and analysis the mechanism of CYP2E1 involved in the regulation of myocardial ketone bodies and energy, including the mechanism of CYP2E1 on ketone bodies catabolism, the mechanism of CYP2E1 on myocardial energy supply and consume, the effect of CYP2E1 on myocardial contraction,the effect of CYP2E1 on mitochondria morphology and enzyme activities. So we can understand more about the biological function of CYP2E1 on heart through this research, and these might be a therapeutic strategy to heart diseases.

CYP2E1主要参与内源物质及药物的代谢。而最近发现CYP2E1在心肌缺血，心肌病及高血压中表达上调，我们前期也证实CYP2E1通过诱导氧化应激及心肌凋亡促进心肌病病理进程，抑制CYP2E1表达可逆转这一病理过程。然而在心脏病理情况下机体为何提高CYP2E1的表达，其高表达是否具有重要生理意义是一个尚未解决科学问题。发现心衰及低氧等心血管疾病时酮体水平及代谢增加，而酮体可诱导CYP2E1活化，我们的假说是CYP2E1可通过诱导酮体代谢从而参与心肌供能。本题拟利用已有心脏特异性过表达及敲低的CYP2E1小鼠分析其参与心肌酮体利用与能量代谢调节的机制，包括CYP2E1对心肌酮体代谢的调控研究；参与心肌总能量消耗及供应的调控研究；对心肌收缩力的调节研究；对心肌线粒体形态及关键酶活影响。最终确定在心脏中于凋亡和能量调节这一平衡中CYP2E1扮演的角色，为其生物学功能研究及临床心脏病治疗提供依据。

CYP2E1主要参与多种内外源物质的代谢活化。研究发现CYP2E1在心肌缺血，心肌病及高血压中表达上调，我们前期也证实CYP2E1通过诱导氧化应激及心肌凋亡促进心肌病病理进程，抑制CYP2E1表达可逆转这一病理过程。然而在心脏病理情况下机体为何提高CYP2E1表达，其高表达是否具有重要生理意义是一个尚未解决的科学问题。所以在本项目中我们利用已有的心脏特异性过表达及敲低的CYP2E1小鼠分析其参与心肌酮体代谢供能与心肌收缩力的关系及参与能量调节的机制。最终通过该项目我们发现CYP2E1于体内及体外心肌缺血模型中表达上调，CYP2E1过表达可使左室内径增加，室壁变薄，心功能下降，而CYP2E1敲低后可使左室内径下降，室壁增厚，心功能增加；心肌缺血时Erk1/2及PI3K/Akt信号通路激活，并确定了心肌缺血时诱导CYP2E1表达上调的目标基因myc，CYP2E1增加心肌ATP生成，同时增加心肌氧化应激。已发表SCI论文1篇，核心期刊论文2篇。通过该项目初步确定了在心脏中于凋亡和能量调节这一平衡中CYP2E1扮演的角色，为其生物学功能研究及临床心脏病的治疗提供了依据。