Research progress of autophagy in heart failure

Abstract

Heart failure poses a significant threat to global public health within the realm of cardiovascular diseases. Its pathological progression involves various alterations in cardiomyocytes, among which autophagy, a crucial intracellular degradation mechanism, plays a pivotal role. Autophagy facilitates the breakdown of damaged organelles and proteins, thereby maintaining cellular homeostasis. In the context of heart failure, autophagy coexists with apoptosis and necrosis, influencing myocardial hypertrophy and ventricular remodeling. However, its impact on heart failure manifests a dual nature: moderate autophagy aids in cardiac repair, whereas excessive autophagy may exacerbate ventricular remodeling and cell demise. This review delves into the fundamental biology of autophagy, elucidating its involvement in the pathological cascade of heart failure and its correlation with cardiac hypertrophy and ventricular remodeling. Furthermore, an analysis of the interplay between autophagy regulatory factors and heart failure sheds light on the potential therapeutic implications of autophagy in the prevention and management of heart failure. This exploration provides a theoretical foundation for novel treatment strategies in combating heart failure.

Keywords: Heart failure; autophagy; cardiomyocyte.

Figure 1

Induction stage of autophagy. During the induction phase of macroautophagy, starvation triggers the activation of AMPK and inactivation of mTOR. Activated AMPK then catalyzes the phosphorylation of the ULK1 complex, which leads to the promotion of autophagy. Integral to this process is the class III PI3K complex, composed of essential components such as hVps34, Beclin-1 (the mammalian homologue of yeast Atg6), p150 (the mammalian homologue of yeast Vps15), and ATG14-like proteins (Atg14L or Barkor). These proteins are all required for the successful induction of autophagy.

Figure 2

Assembly stages of autophagosomes. In the assembly phase of macroautophagy, upstream signaling induces the formation of the ATG12-ATG5 complex. Specifically, ATG12 and ATG5 are catalyzed by ATG7 and ATG10, respectively, to form this complex. The ATG12-ATG5 complex subsequently associates with ATG16L to participate in the assembly of autophagy vesicles. Concurrently, the C-terminal of LC3/Atg8 is proteolytically cleaved by Atg4 to generate cytoplasmic LC3-I. This LC3-I then covalently attaches to phosphatidylethanolamine via the action of ATG7 and ATG3, forming membrane-bound LC3-II. LC3-II subsequently binds to the autophagosome membrane, facilitating its assembly and maturation.

Figure 3

Fusion stage of autophagosome. In the fusion stage of macroautophagy, the autophagosome and lysosome fuse via the interaction between STX17 on the autophagosome membrane and VAMP8 on the lysosome membrane. This fusion process ultimately results in the formation of the autophagolysosome. Following fusion, the contents of the autophagolysosome are degraded, contributing to cellular homeostasis and self-renewal.