热休克转录因子1介导有氧运动对压力超负荷致心肌重构的保护作用及机制研究

Exercise training had a beneficial effect on cardiac remodeling and attenuated heart failure in hypertension, with these effects likely being attributable to the attenuation of cardiac apoptosis and restoration of coronary angiogenesis. However the mechanism underlying such efficacy had remained incomplete. Our latest trials showed that exercise protected heart after pressure overload and it was accompanied by upregulation of heat shock transcription factor-1(HSF-1). There were firm evidences from our previous trials that HSF-1 played a critical inhibiting role in pressure overload- induced cardiac remodeling through attenuating of cardiac apoptosis and promoting myocardial angiogenesis. In view of its crital roles in adaptive cardiac hypertrophy induced by exercise, combined with our previous evidence, we make a guess: upregulation of heat shock transcription factor-1 plays a critical role in cardioprotective effect induced by regular exercise after pressure overload through attenuating of cardiac apoptosis and promoting myocardial angiogenesis. On the basis of this newly discovered link between exercise, autophagy and altered metabolism, we speculate that autophagy may represent a cellular mechanism by which exercise protects heart after pressur overload. We will focuse on HSF-1 and improve our understanding of the molecular basis for exercise-induced cardioprotection. First of all, we will compare the effect of exercise on cardiac histological morphology and function, cardiac apoptosis and myocardial angiogenesis during the different periods after pressure overload. Meanwhile the link between HSF-1, autophagy and extent of exercise-induced cardioprotection will be analysised. Then HSF1 deficient male mice will be used to investigated the role of HSF-1 in cardioprotective effect of exercise after Pressure Overload. Taken together, we will verify our hypothesis:(1)Exercise mediates its cardioprotective effects, in part, by upgulation of HSF-1 and induction and regulation autophagy.(2) Upregulation of heat shock transcription factor-1 plays a critical role in cardioprotective effect induced by regular exercise after pressure overload through inhibiting cardiac apoptosis, altering autophagy and promoting myocardial angiogenesis.

运动能延缓高血压心肌重构已被证实，但机制不明。本课题组最新究显示：运动改善压力超负荷诱导的心肌重构，伴有热休克转录因子（HSF-1）表达增加。鉴于HSF-1是运动诱导生理性心肌肥厚的关键因子，并结合前期成果：HSF-1通过增加心肌血管新生、减少凋亡延缓压力超负荷致心肌重构。推测HSF-1可能通过两个环节在运动延缓心肌重构中起关键作用。本课题关注最新焦点--运动增加自噬是运动健身的重要分子机制，在前期研究基础上，以HSF-1为研究核心，对运动保护心肌重构作用及机制进行更新的诠释。从心脏整体、组织、细胞和分子水平深入探讨运动对心肌重构不同时期的干预效果，及与HSF-1/HSPs、自噬的关系，是课题需要解决的首要问题。以此为基础，应用HSF-1基因敲除鼠，揭示运动作用机制。验证假说：运动上调HSF-1和调节自噬改善压力超负荷致心肌重构；HSF-1通过抑制心肌细胞凋亡、调节自噬、促进血管新生起作用

本研究以热休克转录因子（HSF-1）为研究核心，从心肌微血管新生、凋亡及自噬环节阐明运动对病理性心肌重构的保护机制。研究分为：1.探索运动预适应干预压力超负荷致心肌重构的模型，以及运动干预病理型心肌重构进程模型；2.研究运动预干预以及心肌重构不同时间段的运动干预效果；3.探讨运动对内源性心肌保护因子HSF-1/HSPs以及病理性心肌结构功能、微血管新生、自噬的影响；4.在前期研究基础上，应用HSF-1基因敲除小鼠，从微血管新生、凋亡自噬环节研究运动干预的内源性心肌保护因子HSF-1机制。获得的主要研究结果：1.摸索建立了运动有效干预病理性心肌重构的预干预模型以及进程中干预模型。采用主动脉缩窄（TAC）建立的高血压模型成功，血压稳定， 2周TAC处于代偿期，4周TAC进去失代偿期，8-10周TAC心衰明显。建立了从心肌代偿到失代偿、心衰期，渐进性中等强度运动（11米/分→15米/分，时间30→60分，5次/周）的有效干预模型。2.运动能不同成程度的改善心肌重构早、中及后期病理性心肌重构：改善室壁病理性肥厚、延缓心肌纤维化、改善心肌功能，运动预干预效果明显。3.运动能不同程度的上调HSF-1、血管新生基因VEGF、HIF-1、Ang-1mRNA水平以及蛋白表达，增加TAC心肌减少的微血管；调节自噬基因Beclin-1、LC3、Bax、P53的表达，抑制凋亡、自噬。运动预干预效果优，尤其是对血管新生调节。4.运动对骨骼肌毛细血管新生的影响以及骨骼肌面积的增加，可发挥一定的心肌保护作用。5.生理条件下，HSF-1+/-小鼠在心肌细胞大小、心脏结构形态和心肌收缩功能等方面无明显差异，但HSF-1缺失加速了压力超负荷心肌重构进程，与心肌细胞凋亡、心肌细胞自噬增加、微血管生成减少有关。6. HSF-1缺失削弱了运动延缓病理性心肌重构的作用。运动逆转心肌纤维化、增加心肌微血管新生、减少凋亡自噬作用减弱或消失（相对野生TAC的运动干预效果）。结论：运动激发内源性心肌保护因子——热休克转录因子-1是运动干预压力超负荷心肌重构的重要机制。运动通过HSF-1调节心肌微血管新生、自噬发挥心肌保护作用。