Autophagy in ischemic heart disease

Abstract

Autophagy is a major catabolic pathway by which mammalian cells degrade and recycle macromolecules and organelles. It plays a critical role in removing protein aggregates, as well as damaged or excess organelles, to maintain intracellular homeostasis and to keep the cell healthy. In the heart, autophagy occurs at low levels under normal conditions, and defects in this process cause cardiac dysfunction and heart failure. However, this pathway is rapidly upregulated under environmental stress conditions, including ATP depletion, reactive oxygen species, and mitochondrial permeability transition pore opening. Although autophagy is enhanced in various pathophysiological conditions, such as during ischemia and reperfusion, the functional role of increased autophagy is not clear and is currently under intense investigation. In this review, we discuss the evidence for autophagy in the heart in response to ischemia and reperfusion, identify factors that regulate autophagy, and analyze the potential roles autophagy might play in cardiac cells.

Figure 1

Ubiquitin-like conjugation systems are required for autophagosome formation. In the first case, Atg7 and Atg10 are responsible for conjugating Atg12 onto the acceptor lysine of Atg5. This is a pre-requisite for the recruitment of Atg8, which is conjugated onto phosphatidylethanolamine in the phagophore membrane in a reaction dependent upon Atg7 and Atg3.

Figure 2

GFP-LC3 is present diffusely in the cytoplasm until it is incorporated into the developing autophagosomal membrane. The accumulation of GFP-LC3 on these structures can be visualized by fluorescence microscopy as bright fluorescent puncta. Fusion with the lysosome can be prevented with chloroquine (CQ) or Bafilomycin A1. Selective disruption of autophagy can be accomplished by using a point mutant of Atg5 in which the acceptor lysine is mutated to arginine (Atg5K130R). This prevents the incorporation of Atg12 and stalls the process before incorporation of LC3, phagophore enlargement, or target engulfment.