左心室辅助装置（LVAD）预防心梗后心肌重构和心衰发生的分子机制研究

Myocardial infarction (MI) and the following heart failure is one of the leading causes of death and disability worldwide.Left ventricular assist devices (LVADs) are currently used to provide the circulatory support to the cardiogenic shock patients as rescue therapy or bridge patients with end-stage heart failure to transplantation or recovery, or as destination therapy.We have demonstratedthat acute short-term mechanical unloading using a micro LVAD can prevent cardiac remodeling after MI in a large animal model, which is established by our group. However, the molecular mechanism of the early mechanical unloading after acute MI and following remodelingis unclear. Mitochondria is the "energy factury" of cells. The AMPK-PGC-1α molecular pathway and mitochondrial biogenesis plays an important role in the post-MI remodeling and the development of heart failure.Therefore, in the present study, we will use the MI+LVAD sheep animal model and investigate the mitochondrial biogenesis and mitochondrial function in the infarcted heart and the protective effect of the mechanical unloading. Theheterotopic heart transplantation animal model is a well-known mechanical unloading rodent animal model. Therefore, we will perform heterotopic heart transplantation in AMPK, PGC-1α knock out mice or gene-transferred mice. The SiRNA technique will also be used to demonstrate the role of the AMPK-PGC-1α pathway in the preventive effect of the early mechanical unloading on the post-MI remodleing. A magnetic China-made LVAD, which the applicant is a co-inventor, will be used in this study. This study will improve our understanding of the molecular mechanism of this novel MI therapy and will be helpful for the development of the natioanl LVAD and the future LVAD application in China.

心肌梗死以及心梗后心衰是严重危及人类健康的疾病。左心室辅助装置（LVAD）在临床应用于心源性休克和终末期心衰的循环支持、心衰逆转以及永久性植入治疗。申请人在国际上首先建立了大动物心梗+LVAD植入模型，首先发现心梗后早期应用LVAD可以减缓心梗后心肌重构和心衰发生。目前这一心衰防治新策略的机制未明。线粒体是细胞的"能量工厂"，AMPK-PGC-1α通路及其调控的线粒体生物合成是心肌重构和心衰发生的重要分子机制。本课题将应用羊心梗+LVAD植入模型，研究LVAD对心梗后心肌线粒体生物合成障碍的保护作用；并应用异位心脏移植心室减负模型，通过AMPK/PGC-1α基因敲除、转基因、SiRNA等方法，确定LVAD是否通过AMPK-PGC-1α通路实现其心肌保护作用。本课题将应用申请人在国内联合研制的磁悬浮LVAD进行动物实验，深入LVAD预防心梗后心肌重构分子机制,促进我国LVAD的研发和应用。

心肌梗死及心梗后心衰是严重危及人类健康的重大疾病之一。左心室辅助装置（LVAD）是临床上治疗心源性休克和终末期心衰的循环支持、心衰逆转等心血管疾病有效手段。本课题采用羊心梗+LVAD植入模型，研究LVAD对心梗后心肌线粒体生物合成障碍的保护作用。.研究发现：1）建立正常羊LVAD植入模型，验证不同时间点AMPK/PGC-1α相关蛋白的表达，发现机械减负保护心肌细胞线粒体生物合成和功能；2）建立羊心梗以及LVAD植入模型，观察发现LVAD植入显著降低左心室舒张末容积（EDV）及左心室收缩末容积（ESV），增加心脏射血分数（EF值）；3）超声心动图结果表明LVAD植入显著保护心脏功能、减少心梗面积，同时，HE染色结果表明LVAD机械减负显著减小了心肌细胞的肥大； 4）采用Western blot检测心肌细胞凋亡相关的蛋白表达，发现LVAD植入明显减少心梗引起的calcineurin、p-BAD、cytochrome c以及凋亡因子caspase-3的高表达； 5）采用心脏异位移植手术，将PGC-1α基因敲除（PGC-1α KD）小鼠的冠状动脉结扎造成大面积心梗作为供体心脏，移植于同品系正常小鼠。观察发现，与野生型腹腔异位移植的心脏相比，移植PGC-1α KD心脏组的心肌细胞显著凋亡，AMPK-PGC-1α相关蛋白以及凋亡相关蛋白表达显著降低。 .研究结果：通过羊心梗+LVAD植入模型及PGC-1α KD小鼠心脏异位移植模型，发现LVAD植入明显防治心肌重构和心衰发生，且AMPK-PGC-1α通路及其调控的线粒体生物合成是LVAD机械减负防治心梗的重要分子机制，为临床应用提供重要的理论基础。