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Rheb is a Critical Regulator of Autophagy During Myocardial Ischemia: Pathophysiological Implications in Obesity and Metabolic Syndrome

SCIARRETTA, Sebastiano ; ZHAI, Peiyong ; DAN SHAO ; MAEJIMA, Yasuhiro ; ROBBINS, Jeffrey ; VOLPE, Massimo ; CONDORELLI, Gianluigi ; SADOSHIMA, Junichi

Circulation (New York, N.Y.), 2012-03, Vol.125 (9), p.1134-1146 [Periódico revisado por pares]

Hagerstown, MD: Lippincott Williams & Wilkins

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Título:
Rheb is a Critical Regulator of Autophagy During Myocardial Ischemia: Pathophysiological Implications in Obesity and Metabolic Syndrome
Autor: SCIARRETTA, Sebastiano ; ZHAI, Peiyong ; DAN SHAO ; MAEJIMA, Yasuhiro ; ROBBINS, Jeffrey ; VOLPE, Massimo ; CONDORELLI, Gianluigi ; SADOSHIMA, Junichi
Assuntos: Animals ; Apoptosis Regulatory Proteins - genetics ; Apoptosis Regulatory Proteins - metabolism ; Autophagy - physiology ; Beclin-1 ; Biological and medical sciences ; Blood and lymphatic vessels ; Cardiology. Vascular system ; Cardiovascular system ; Cell Survival - physiology ; Cells, Cultured ; Dietary Fats - pharmacology ; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous ; Endoplasmic Reticulum Stress - physiology ; Energy Metabolism - physiology ; Glucose - pharmacology ; Medical sciences ; Metabolic Syndrome - metabolism ; Metabolic Syndrome - pathology ; Metabolic Syndrome - physiopathology ; Mice ; Mice, Knockout ; Monomeric GTP-Binding Proteins - genetics ; Monomeric GTP-Binding Proteins - metabolism ; Myocardial Ischemia - metabolism ; Myocardial Ischemia - pathology ; Myocardial Ischemia - physiopathology ; Myocytes, Cardiac - cytology ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - physiology ; Neuropeptides - genetics ; Neuropeptides - metabolism ; Obesity - metabolism ; Obesity - pathology ; Obesity - physiopathology ; Pharmacology. Drug treatments ; Ras Homolog Enriched in Brain Protein ; Rats ; Signal Transduction - physiology ; TOR Serine-Threonine Kinases - genetics ; TOR Serine-Threonine Kinases - metabolism ; Vasodilator agents. Cerebral vasodilators
É parte de: Circulation (New York, N.Y.), 2012-03, Vol.125 (9), p.1134-1146
Descrição: Rheb is a GTP-binding protein that promotes cell survival and mediates the cellular response to energy deprivation (ED). The role of Rheb in the regulation of cell survival during ED has not been investigated in the heart. Rheb is inactivated during cardiomyocyte (CM) glucose deprivation (GD) in vitro, and during acute myocardial ischemia in vivo. Rheb inhibition causes mTORC1 inhibition, because forced activation of Rheb, through Rheb overexpression in vitro and through inducible cardiac-specific Rheb overexpression in vivo, restored mTORC1 activity. Restoration of mTORC1 activity reduced CM survival during GD and increased infarct size after ischemia, both of which were accompanied by inhibition of autophagy, whereas Rheb knockdown increased autophagy and CM survival. Rheb inhibits autophagy mostly through Atg7 depletion. Restoration of autophagy, through Atg7 reexpression and inhibition of mTORC1, increased cellular ATP content and reduced endoplasmic reticulum stress, thereby reducing CM death induced by Rheb activation. Mice with high-fat diet-induced obesity and metabolic syndrome (HFD mice) exhibited deregulated cardiac activation of Rheb and mTORC1, particularly during ischemia. HFD mice presented inhibition of cardiac autophagy and displayed increased ischemic injury. Pharmacological and genetic inhibition of mTORC1 restored autophagy and abrogated the increase in infarct size observed in HFD mice, but they failed to protect HFD mice in the presence of genetic disruption of autophagy. Inactivation of Rheb protects CMs during ED through activation of autophagy. Rheb and mTORC1 may represent therapeutic targets to reduce myocardial damage during ischemia, particularly in obese patients.
Editor: Hagerstown, MD: Lippincott Williams & Wilkins
Idioma: Inglês

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Rheb is a Critical Regulator of Autophagy During Myocardial Ischemia: Pathophysiological Implications in Obesity and Metabolic Syndrome

SCIARRETTA, Sebastiano ; ZHAI, Peiyong ; DAN SHAO ; MAEJIMA, Yasuhiro ; ROBBINS, Jeffrey ; VOLPE, Massimo ; CONDORELLI, Gianluigi ; SADOSHIMA, Junichi

Hagerstown, MD: Lippincott Williams & Wilkins

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