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.