The role of autophagy in cardiac hypertrophy

Abstract

Autophagy is conserved in nature from lower eukaryotes to mammals and is an important self-cannibalizing, degradative process that contributes to the elimination of superfluous materials. Cardiac hypertrophy is primarily characterized by excess protein synthesis, increased cardiomyocyte size, and thickened ventricular walls and is a major risk factor that promotes arrhythmia and heart failure. In recent years, cardiomyocyte autophagy has been considered to play a role in controlling the hypertrophic response. However, the beneficial or aggravating role of cardiomyocyte autophagy in cardiac hypertrophy remains controversial. The exact mechanism of cardiomyocyte autophagy in cardiac hypertrophy requires further study. In this review, we summarize the controversies associated with autophagy in cardiac hypertrophy and provide insights into the role of autophagy in the development of cardiac hypertrophy. We conclude that future studies should emphasize the relationship between autophagy and the different stages of cardiac hypertrophy, as well as the autophagic flux and selective autophagy. Autophagy will be a potential therapeutic target for cardiac hypertrophy.

Keywords: autophagic flux; autophagy; cardiac function; cardiac hypertrophy; cell signaling.

Figure 1.

Process of macroautophagy The process of macroautophagy consists of four steps: induction and nucleation, elongation and expansion, fusion, and degradation. Several autophagy-related (Atg) proteins are recruited to govern the processes of autophagy.

Figure 2.

Stimuli-induced autophagy promotes cardiac hypertrophy (A) Transverse aortic constriction (TAC), pulmonary arterial hypertension (PAH), renovascular hypertension, static pressure, and mechanical stress induce marked heart hypertrophy, accompanied by high levels of autophagic responses in the heart. (B) Cold stress, high-fat/sucrose diet (HFSD), chronic alcohol intake, exercises, and cathepsin-L deficient appear to play roles in regulating autophagy during the development of cardiac hypertrophy.

Figure 3.

Inhibited autophagy reverses cardiac hypertrophy Adiponectin receptor 1 (AdipoR1), FA, valsartan, and TSA decrease the cardiac autophagy level and exhibit positive effects on cardiac hypertrophy.

Figure 4.

Several stimuli deteriorate cardiac hypertrophy by decreasing autophagy Aging, high-fat diet, miRNA-221, miRNA-212/13, Atg5 deficiency, PTEN deletion, and MIF deficiency induce cardiac hypertrophy and down-regulate autophagy.

Figure 5.

High level of autophagy ameliorates cardiac hypertrophy Regulated in development and DNA damage 1 (REDD1), intermedin (IMD), 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), metformin, catalase, rapamycin, berberine, destretch, doxycycline, and transcriptional regulator p8 deletion significantly increase autophagy level, improve cardiac function, and attenuate cardiac hypertrophy.