Ghrelin通过调节自噬改善心肌肥厚的机制研究

Ghrelin, the endogenous ligand of growth hormone secretagogue receptor (GHS-R), plays an important role in the regulation of energy balance and exerts cardioprotective effect. It has been reported to protect heart againt cardiac hypertrophy, but its potential mechanism of action is unknown. Recent studies have shown that enhancing autophagy favorably attenuates cardiac hypertrophy. And activation of AMP-activated protein kinase (AMPK) promotes autophagy, while ghrelin could activate AMPK in heart. We therefore proposed the hypothesis that ghrelin may attenuate cardiac hypertrophy by promoting autophagy via activation of AMPK. Here in cardiac hypertrophy model in vivo and in vitro we aimed to determine :1) the expression of ghrelin and its receptors in cardiac hypertrophy, and the effect of ghrelin on cardiac hypertrophy; 2)whether ghrelin inhibited cardiac hypertrophy by promoting autophagy；3）whether ghrelin promoted autophagy through activating AMPK；4）the possible signaling pathway of ghrelin activating AMPK and autophagy in cardiac hypertrophy. The present study might provide further insight into developing new therapeutic approaches against cardiac hypertrophy, which has important theoretical significance and potential application value.

Ghrelin是一种具有改善能量代谢和心血管保护作用的活性多肽。最新研究报告，ghrelin能够抑制心肌肥厚，但机制尚不清楚。自噬是真核生物体内一种高度保守的细胞内降解过程，具有维持细胞稳态的作用。研究发现，激活自噬可以减轻心肌肥厚。能量感受分子单磷酸腺苷活化蛋白激酶（AMPK）的激活可以促进自噬，而ghrelin能够激活AMPK。因此提出如下假说：ghrelin可能通过激活AMPK促进心肌细胞自噬，进而抑制心肌肥厚。本项目在整体和离体心肌肥厚模型上，以自噬为切入点：1) 阐明ghrelin及其受体在心肌肥厚中的变化及作用；2）确定ghrelin是否通过激活自噬改善心肌肥厚；3)确定ghrelin激活心肌肥厚时自噬的分子靶点是否为AMPK；4）确定ghrelin激活AMPK及自噬的受体及受体后信号通路，为早期预防与逆转心肌肥厚提供一个可调控的靶标，具有重要理论意义和潜在应用价值。