Autophagy is impaired in cardiac ischemia-reperfusion injury.
Accumulating evidence attests to a prosurvival role for autophagy under stress, by facilitating removal of damaged proteins and organelles and recycling basic building blocks, which can be utilized for energy generation and targeted macromolecular synthesis to shore up cellular defenses. These observations are difficult to reconcile with the dichotomous prosurvival and death-inducing roles ascribed to macroautophagy in cardiac ischemia and reperfusion injury, respectively. A careful reexamination of 'flux' through the macroautophagy pathway reveals that autophagosome clearance is markedly impaired with reperfusion (reoxygenation) in cardiomyocytes following an ischemic (hypoxic) insult, resulting from reactive oxygen species (ROS)-mediated decline in LAMP2 and increase in BECN1 abundance. This results in impaired autophagy that is 'ineffective' in protecting against cell death with ischemia-reperfusion injury. Restoration of autophagosome clearance and by inference, 'adequate' autophagy, attenuates reoxygenation-induced cell death.
Center for Cardiovascular Research, Division of Cardiology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Xiucui
X
Ma
Haiyan
H
Liu
Sarah R
SR
Foyil
Rebecca J
RJ
Godar
Carla J
CJ
Weinheimer
Abhinav
A
Diwan
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000235:genetics; D000071186:Beclin-1; D053263:Gene Regulatory Networks / Q000235:genetics; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D015428:Myocardial Reperfusion Injury / Q000473:pathology*; D010588:Phagosomes / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D017382:Reactive Oxygen Species