The importance of autophagy in cardioprotection.
Autophagy is an intracellular lysosomal-mediated catabolic process in which senescent or damaged proteins and organelles are sequestered by double membrane-limited vesicles called autophagosomes, and then degraded by lysosomes. While the role of autophagy in different pathological states is context-dependent, it has been shown that during cardiac ischemia, autophagy is upregulated as a cardioprotective adaptation. We recently demonstrated that Rheb, a small GTP-binding protein that directly activates the complex 1 of the mechanistic target of rapamycin, is a critical regulator of autophagy during cardiac ischemia. We found that cardiac Rheb/mTORC1 signaling is activated in a deregulated manner during ischemia in obesity and metabolic syndrome. This uncontrolled activation of the Rheb/mTORC1 pathway leads to autophagy inhibition and to a reduction of myocardial tolerance to ischemia. This data further supports the relevance of autophagy as a fundamental protective mechanism during myocardial ischemia and suggests that reactivation of autophagy, in particular through the inhibition of Rheb/mTORC1 signaling may represent a promising therapeutic option to treat subjects with an acute myocardial infarction, particularly those affected by metabolic derangements. This review will deal with the biological significance of autophagy in cardioprotection.
Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA, sebastianosciarretta@yahoo.it.
Sebastiano
S
Sciarretta
Derek
D
Yee
Varun
V
Shenoy
Narayani
N
Nagarajan
Junichi
J
Sadoshima
D001343:Autophagy / Q000502:physiology*; D006333:Heart Failure / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D008247:Lysosomes / Q000502:physiology; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology; D046912:Multiprotein Complexes / Q000502:physiology; D009203:Myocardial Infarction / Q000503:physiopathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000503:physiopathology / Q000517:prevention & control*; D009479:Neuropeptides / Q000502:physiology; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
D046912:Multiprotein Complexes; D009479:Neuropeptides; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins