title: Cardiac mTOR rescues the detrimental effects of diet-induced obesity in the heart after ischemia-reperfusion.
abstract: Diet-induced obesity deteriorates the recovery of cardiac function after ischemia-reperfusion (I/R) injury. While mechanistic target of rapamycin (mTOR) is a key mediator of energy metabolism, the effects of cardiac mTOR in ischemic injury under metabolic syndrome remains undefined. Using cardiac-specific transgenic mice overexpressing mTOR (mTOR-Tg mice), we studied the effect of mTOR on cardiac function in both ex vivo and in vivo models of I/R injury in high-fat diet (HFD)-induced obese mice. mTOR-Tg and wild-type (WT) mice were fed a HFD (60% fat by calories) for 12 wk. Glucose intolerance and insulin resistance induced by the HFD were comparable between WT HFD-fed and mTOR-Tg HFD-fed mice. Functional recovery after I/R in the ex vivo Langendorff perfusion model was significantly lower in HFD-fed mice than normal chow diet-fed mice. mTOR-Tg mice demonstrated better cardiac function recovery and had less of the necrotic markers creatine kinase and lactate dehydrogenase in both feeding conditions. Additionally, mTOR overexpression suppressed expression of proinflammatory cytokines, including IL-6 and TNF-α, in both feeding conditions after I/R injury. In vivo I/R models showed that at 1 wk after I/R, HFD-fed mice exhibited worse cardiac function and larger myocardial scarring along myofibers compared with normal chow diet-fed mice. In both feeding conditions, mTOR overexpression preserved cardiac function and prevented myocardial scarring. These findings suggest that cardiac mTOR overexpression is sufficient to prevent the detrimental effects of diet-induced obesity on the heart after I/R, by reducing cardiac dysfunction and myocardial scarring.
authors.affiliation: Department of Anatomy, Biochemistry and Physiology, Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Aoyagi
authors.affiliation: Department of Anatomy, Biochemistry and Physiology, Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Higa
authors.affiliation: Department of Anatomy, Biochemistry and Physiology, Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Aoyagi
authors.affiliation: Department of Anatomy, Biochemistry and Physiology, Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
authors.forename: Naaiko
authors.initials: N
authors.lastname: Yorichika
authors.affiliation: Department of Anatomy, Biochemistry and Physiology, Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
authors.forename: Briana K
authors.initials: BK
authors.lastname: Shimada
authors.affiliation: Department of Anatomy, Biochemistry and Physiology, Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii tmatsui@hawaii.edu.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsui
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018149:Glucose Intolerance / Q000201:enzymology / Q000209:etiology; D018836:Inflammation Mediators / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009336:Necrosis; D009765:Obesity / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D016277:Ventricular Function, Left; D017725:Ventricular Pressure; D020257:Ventricular Remodeling; D015430:Weight Gain
chemical_list: D018836:Inflammation Mediators; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases
keywords: diet-induced obesity; heart failure; mammalian target of rapamycin; metabolic syndrome; myocardial infarction; transgenic mice