Targeting Autophagy in Atrial Fibrillation

Abstract

Atrial fibrillation (AF) is the most common type of arrhythmia in clinical practice, and its incidence is positively correlated with risk factors that include advanced age, hypertension, diabetes, and heart failure. Although our understanding of the mechanisms that govern the occurrence and persistence of AF has been increasing rapidly, the exact mechanism of AF is still not fully understood. Autophagy is an evolutionarily highly conserved and specific physiological process in cells that has been suggested as a potential therapeutic target for several cardiovascular diseases including the pathophysiology of AF. The present article provides an updated review of the fast-progressing field of research surrounding autophagy in AF, and how regulating autophagy might be a therapeutic target to reduce the incidence of AF.

Keywords: atrial anatomical remodeling; atrial electrical remodeling; atrial fibrillation; autophagy; energy metabolism remodeling.

Fig. 1.

Schematic model of the major pathways of the autophagic mechanisms. (A) Macroautophagy of intracellular substances includes initiation, elongation, closure, maturation, and degradation. The endoplasmic reticulum, Golgi apparatus, mitochondria, and plasma membranes are membrane sources of autophagic vesicles. The Ulk macromolecular complex promotes the initiation of the phagophore, thereby regulating PI3P formation to control nascent autophagosomes. Varieties of autophagy-related proteins are involved in this process. The autophagosome sequesters proteins, both misfolded and unfolded, and defective mitochondria. After maturation, autophagosomes fuse with lysosomes to form the autolysosome where the contents are degraded by acid hydrolases. (B) In microautophagy, lysosomes directly engulf cellular components. (C) In CMA, Hsc70 transports the target protein to the lysosome for degradation. ULK (UNC51-like) enzymes are a family of mammalian kinases that have critical roles in autophagy and development. PI3P, phosphatidyl inositol triphosphate; Atg, autophagy related gene; LC3, microtuble-associated protein light chain 3; ER, endoplasmic reticulum; Hsc, heat-shock cognate protein; LAMP, lysosome-associated membrane glycoprotein; CMA, chaperone-mediated autophagy; Hsc70, heat shock cognate 70.

Fig. 2.

Schematic diagram of autophagy involved in atrial electrical remodeling (AER). Rapid atrial rates increase the influx of ${\mathrm{Ca}}^{2+}$ into atrial cells at each action potential, leading to calcium overload, and then inducing atrial fibrillation (AF). AF can also lead to calcium overload. Activated autophagy induced by rapid atrial rates and ERS induces a decrease in action potential duration (APD) and a shortened atrial effective refractory period (AERP) via ubiquitin-dependent selective degradation of Ical. Shortened APD and atrial fibrillation reinforce each other in a vicious cycle. Activated autophagy promotes connexin degradation, leading to different impedances and conduction velocities between cardiomyocytes, resulting in micro-reentrant and inducing AF. ERS, endoplasmic reticulum stress; Ical, L-type calcium channel; Cx, connexin.

Fig. 3.

Schematic diagram of autophagy involved in atrial anatomical remodeling (AAR). Autophagy may exert a dual role in regulating the extracellular matrix in myocardial fibrosis. Myocardial fibrosis can impede electric propagation, favoring reentry. Either autophagy activation or inhibition may promote atrial fibrillation. ROS, reactive oxygen species; Ang II, angiotensin II; TGF-$\beta$1, transforming growth factor-$\beta$1; LC3, microtuble-associated protein light chain 3; ECM, extracellular matrix; OPN, osteopontin; AMPK, adenosine $5^{\prime }$-monophosphate (AMP)-activated protein kinase; APN, adiponectin; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; LA, left atrial; AF, atrial fibrillation.

Fig. 4.

Schematic diagram of autophagy involved in proteostasis and mitochondrial function. (A) Autophagy protects cardiomyocytes from atrial fibrillation (AF) by degrading unfolded and misfolded proteins. But there are other views that ERS-induced autophagy also increases AF susceptibility by aggravating myocardial fibrosis. (B) Rapid atrial pacing leads to mitochondrial fragmentation and impaired function, which in turn leads to increased mt-ROS and decreased ATP. Impaired mitophagy causes a decrease in dysfunctional mitochondria as the potential mechanisms. mt-ROS, mitochondrial reactive oxygen species; TGF-$\beta$1, transforming growth factor-$\beta$1; ATP, adenosine-triphosphate; ERS, endoplasmic reticulum stress.