1. Introduction
Cardiac hypertrophy, defined as increased heart mass and the ratio of heart weight to body weight, is a primary adaptive response in essence [1, 2]. An increase in ventricular wall thickness, the growth of cardiomyocytes in size, and the over-synthesis of ubiquitinated proteins are major hallmarks of cardiac hypertrophy [3-6]. Cardiac hypertrophy involves two dominant types: physiological cardiac hypertrophy and pathological cardiac hypertrophy, which can be affected by many signaling molecules in different phases (Fig. 1).
Physiological cardiac hypertrophy is an adaptive response in cardiac morphology and function, which is associated with normal heart function and usually occurs in physical exercise or pregnancy [7]. Conversely, pathological cardiac hypertrophy is a decompensatory process, which is tightly linked with cardiac insufficiency under stress stimuli or diseases (such as coronary artery disease, hypertension and myocardial infarction) [7-10]. Pathological cardiac hypertrophy continues to increase the pre-and post-load of the heart to develop compensatory hypertrophy into a decompensated process, eventually leading to cardiac arrhythmia, dysfunction, failure, or sudden death [11-13]. Many pathological stimuli, such as activated neurohumoral regulators, hypertension and myocardial damage, can lead to dilate cardiac chambers and promote the progression of heart failure (HF). It has been proposed that about 26 million population suffer from heart failure around the world, and nearly half of the cases have heart failure with reduced ejection fraction (HFrEF) [14, 15]. According to the National Health and Nutrition Examination Survey from 2013 to 2016, approximately 6.2 million adults in the US suffered from heart failure per year [14, 16]. Recently, there is growing evidence that autophagy may specifically regulate cardiac hypertrophy through regulating autophagy-related genes expression and some signaling pathways [3].
Autophagy, also known as “self-eating” in Greek, widely exists in eukaryotic cells [17]. Autophagy is a lysosome-dependent degradation pathway mediated by Atgs , which essentially degrades and recovers cytoplasmic components to maintain cellular homeostasis and provide energy [18, 19]. There are at least three major types of autophagy: macro-autophagy, micro-autophagy, and chaperone-mediated autophagy (CMA) [20]. Macro-autophagy (hereafter referred to as autophagy) characterized by the formation of a distinctive double-membrane structure called the autophagosome is the uppermost type of autophagy [21]. Micro-autophagy is an inward invagination process of the lysosomal membrane and CMA does not contain membrane reorganization process, but mediated by the chaperone hsc70 (heat shock cognate 70), cochaperones, and LAMP-2A (lysosomal-associated membrane protein type 2A) [20]. Notably, autophagy bidirectionally regulates cell survival and death. Basal autophagy degrades damaged organelles and regulates apoptotic proteases to maintain normal cell growth [22]. However, under continuous stress stimuli, the excessive activation of autophagy may lead to cell death [23]. Due to the complicated and bidirectional characteristics of autophagy, the effect (beneficial or harmful) of autophagy in cardiac hypertrophy remains controversial [24, 25].
In this review, we discuss the underlying mechanism of autophagy-related influencing factors for cardiac hypertrophy in existing reports. Subsequently, we analyze the potential effects of current autophagy modulators for pathological cardiac hypertrophy and focus on the advantages and challenges faced by autophagy modulators for the therapy of pathological cardiac hypertrophy.