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- Sebastiano Sciarretta
- From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ (S.S., P.Z., D.S., Y.M., J.S.); IRCCS Neuromed, Pozzilli (IS), Italy (S.S., M.V.); Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH (J.R.); Cardiology Department, IInd School of Medicine, University of Rome “Sapienza,” S. Andrea Hospital, Rome, Italy (M.V.); and...
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- Peiyong Zhai
- From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ (S.S., P.Z., D.S., Y.M., J.S.); IRCCS Neuromed, Pozzilli (IS), Italy (S.S., M.V.); Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH (J.R.); Cardiology Department, IInd School of Medicine, University of Rome “Sapienza,” S. Andrea Hospital, Rome, Italy (M.V.); and...
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- Dan Shao
- From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ (S.S., P.Z., D.S., Y.M., J.S.); IRCCS Neuromed, Pozzilli (IS), Italy (S.S., M.V.); Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH (J.R.); Cardiology Department, IInd School of Medicine, University of Rome “Sapienza,” S. Andrea Hospital, Rome, Italy (M.V.); and...
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- Yasuhiro Maejima
- From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ (S.S., P.Z., D.S., Y.M., J.S.); IRCCS Neuromed, Pozzilli (IS), Italy (S.S., M.V.); Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH (J.R.); Cardiology Department, IInd School of Medicine, University of Rome “Sapienza,” S. Andrea Hospital, Rome, Italy (M.V.); and...
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- Jeffrey Robbins
- From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ (S.S., P.Z., D.S., Y.M., J.S.); IRCCS Neuromed, Pozzilli (IS), Italy (S.S., M.V.); Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH (J.R.); Cardiology Department, IInd School of Medicine, University of Rome “Sapienza,” S. Andrea Hospital, Rome, Italy (M.V.); and...
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- Massimo Volpe
- From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ (S.S., P.Z., D.S., Y.M., J.S.); IRCCS Neuromed, Pozzilli (IS), Italy (S.S., M.V.); Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH (J.R.); Cardiology Department, IInd School of Medicine, University of Rome “Sapienza,” S. Andrea Hospital, Rome, Italy (M.V.); and...
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- Gianluigi Condorelli
- From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ (S.S., P.Z., D.S., Y.M., J.S.); IRCCS Neuromed, Pozzilli (IS), Italy (S.S., M.V.); Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH (J.R.); Cardiology Department, IInd School of Medicine, University of Rome “Sapienza,” S. Andrea Hospital, Rome, Italy (M.V.); and...
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- Junichi Sadoshima
- From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ (S.S., P.Z., D.S., Y.M., J.S.); IRCCS Neuromed, Pozzilli (IS), Italy (S.S., M.V.); Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH (J.R.); Cardiology Department, IInd School of Medicine, University of Rome “Sapienza,” S. Andrea Hospital, Rome, Italy (M.V.); and...
書誌事項
- タイトル別名
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- Pathophysiological Implications in Obesity and Metabolic Syndrome
抄録
<jats:sec> <jats:title>Background—</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>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.</jats:p> </jats:sec>
収録刊行物
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- Circulation
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Circulation 125 (9), 1134-1146, 2012-03-06
Ovid Technologies (Wolters Kluwer Health)