自噬在逆转心肌肥厚中的作用

Ubiquitin-proteasome system(UPS) and/or autophagy, the FOXO transcription factor downstream regulators, is a general pathway of tissue protein degradation. In our previous studies, we found that UPS activation promoted the progression of cardiac hypertrophy and heart failure rather than reversed it. In the preliminary experiments, we found that angiotensin-converting enzyme inhibitor(ACEI, Captopril) reversed cardiac hypertrophy accompanied with up-regulated expressions of FOXO transcription factors and increased autophagy. Basing on these preliminary observations, we hypothesized that ACEI reverses cardiac hypertrophy by activating autophagy, not UPS. The role of autophagy in the reversal of cardiac hypertrophy via blocking renin-angiotensin system(RAS) is still unknown. In the present application we will investigate the effects and potential mechanisms of RAS blocking on the autophagy during different stages of cardiac hypertrophy in the mouse cardiac hypertrophy models induced by transverse aortic constriction (TAC). In addition, we will also investigate the molecular mechanisms underlying autophagy in the reversal of cardiac hypertrophy via using RAS blockers or silencing autophagy related genes with adenovirus transfection in a primary myocardial cell culture setting. The proposal is of translational significance and the anticipated results may provide novel targets for therapeutic reversal of cardiac hypertrophy.

泛素蛋白酶系统(UPS)和/或自噬是机体内所有组织蛋白降解的共同途径，FOXO转录因子是这两大蛋白降解系统的上游调节分子。我们前期研究发现UPS激活不仅不能逆转心肌肥厚，反而会促进心肌肥厚和心衰的进展。且在预实验中我们发现血管紧张素转换酶(ACE)抑制剂(卡托普利)，具有逆转心肌肥厚的作用，同时可激活FOXO转录因子和上调自噬水平。因此我们推测ACE抑制剂逆转心肌肥厚很可能是通过激活自噬而非激活UPS实现的，目前这方面的研究尚未见报道。本研究拟在细胞模型中通过腺病毒转染等技术，上调或沉默自噬相关基因，明确自噬在肾素-血管紧张素系统(RAS)阻断剂逆转心肌肥厚中的作用，进而在动物模型中观察在心肌肥厚不同阶段使用RAS阻断剂对自噬水平调控的时效特征和量效特征，以明确自噬在心肌肥厚不同阶段的效应和机制，阐明自噬是否为心肌肥厚逆转的核心机制，为临床实现心肌肥厚的逆转治疗提供新的药物靶点。

蛋白质合成和降解失衡是调控心肌肥厚的主要机制之一。自噬作为一重要的蛋白降解生物过程，对心肌肥厚具有重要调控作用。我们利用主动脉缩窄术构建小鼠心肌肥厚模型，发现在心肌肥厚过程中自噬水平显著下降。在动物模型中，我们发现RAS抑制剂可以通过上调FOXO1从而激活自噬，最终逆转心肌肥厚。在心肌细胞中，我们发现苯肾上腺素诱导心肌细胞肥厚过程中 ，自噬水平亦呈下降趋势，而腺病毒转染过表达FOXO1可增加自噬水平，并显著逆转心肌细胞肥厚。通过小干扰RNA转染对自噬相关基因Atg7进行敲除进而阻断自噬后，我们发现心肌细胞肥大更明显，而FOXO1过表达对心肌肥厚的逆转作用也被阻断。因此，我们从动物及细胞水平阐明了RAS抑制剂通过对FOXO1的促进作用激活自噬从而逆转心肌肥厚，为心肌肥厚的临床治疗提供新靶点和理论依据