2. Roles of autophagy in cardiac hypertrophy
Pathological cardiac hypertrophy is one of the pathological manifestations of cardiovascular disease remains the world’s leading cause of death. Cardiomyocyte autophagy plays complicated but indispensable roles in helping preserve normal metabolism and function of the heart. Importantly, pieces of evidence have revealed that autophagy plays a critical role in cardiac hypertrophy (Fig. 2). On the one hand, autophagy can act as a pro-survival factor in cardiac hypertrophy. Firstly, autophagy can promote the degradation of aging and damaged organelles, long-lived proteins and misfolded proteins to supply part of the energy needed by the heart. Secondly, some growth hormones such as insulin and IGF-1 (insulin-like growth factor 1), which are the upstream regulator of autophagy, can promote physiological cardiac hypertrophy development [26]. For example, Mcmullen et al.have reported that growth hormones (e.g., insulin) and activated several signaling pathways such as PI3K (phosphoinositide 3-kinase), Akt (protein kinase B), AMPK (AMP-activated protein kinase), and mTOR (mechanistic target of rapamycin), also participate in autophagy pathway [26-28]. Thirdly, autophagy eliminates the ill effects of ROS on cardiomyocytes by removing damaged mitochondria from hypertrophic hearts. On the other hand, autophagy can act as a pro-death factor in cardiac hypertrophy. For instance, Nakai and Taneike et al. found that conditional inactivation of either the Atg5 or Atg7genes in the adult heart, which led to abrogation of autophagy pathways, resulted in rapid onset of cardiac hypertrophy, left ventricular dilation, and diminished cardiac output [25, 29]. Therefore, under physiological conditions, basal autophagy maintains cell metabolic balance by transforming damaged organelles into energy substances (e.g., amino acids) and controlling protein quality, and promotes myocardial survival [30]. However, Qi et al. reported that autophagy flux is markedly induced in a swimming- induced and IGF-1-induced physiological cardiac hypertrophy rat model, which indicated that excessive autophagy was also occurred during cardiac hypertrophy and might be harmful [28, 30, 31].