Autophagy, innate immunity, and cardiac disease

Abstract

Autophagy is an evolutionarily conserved mechanism of cell adaptation to metabolic and environmental stress. It mediates the disposal of protein aggregates and dysfunctional organelles, although non-conventional features have recently emerged to broadly extend the pathophysiological relevance of autophagy. In baseline conditions, basal autophagy critically regulates cardiac homeostasis to preserve structural and functional integrity and protect against cell damage and genomic instability occurring with aging. Moreover, autophagy is stimulated by multiple cardiac injuries and contributes to mechanisms of response and remodeling following ischemia, pressure overload, and metabolic stress. Besides cardiac cells, autophagy orchestrates the maturation of neutrophils and other immune cells, influencing their function. In this review, we will discuss the evidence supporting the role of autophagy in cardiac homeostasis, aging, and cardioimmunological response to cardiac injury. Finally, we highlight possible translational perspectives of modulating autophagy for therapeutic purposes to improve the care of patients with acute and chronic cardiac disease.

Keywords: aging; autophagy; cardiac function; diabetic cardiomiopathy; heterophagy; immune response; myocardial infarction.

FIGURE 1

General mechanisms of macroautophagy. Stress signals activate intracellular metabolic pathways (e.g., mTORC-1, GSK-3β, AMPK) that culminate in the regulation of the ULK1 complex. This complex triggers the initiation of autophagy by promoting phagophore nucleation through the activation of the PI3KC3 complex 1 via the phosphorylation of multiple protein, such as BECLIN1, VPS34, and ATG14. After nucleation, the coordinated activity of multiple ATGs mediates phagophore elongation through the conjugation of proteins of the ATG8-family (e.g., LC3). The phagophore engulfs intracellular cargoes (e.g., protein aggregates and dysfunctional organelles) before membrane sealing to produce a double-layered vesicle named autophagosome, the hallmark of macroautophagy. The autophagosome eventually fuses with a lysosome for the degradation of autophagic cargoes, while membraned are recycled and become available for the elongation of other phagophores (see text for more details).

FIGURE 2

Functional relevance of autophagy for cardiac pathophysiology. Constitutive autophagy of cardiomyocytes under basal conditions is a homeostatic mechanism for normal cardiac structure and function. Autophagic activity is reduced during aging or following exposure to stressors such as chemotherapy drugs owning cardiotoxicity. However, in hearts exposed to hemodynamic overload or ischemia-reperfusion injury, autophagic activity is upregulated at supraphysiological levels, suggesting a contribution to the maladaptive response of the heart that may lead to heart failure.