title: Cardiac mTOR protects the heart against ischemia-reperfusion injury.
abstract: Cardiac mammalian target of rapamycin (mTOR) is necessary and sufficient to prevent cardiac dysfunction in pathological hypertrophy. However, the role of cardiac mTOR in heart failure after ischemic injury remains undefined. To address this question, we used transgenic (Tg) mice with cardiac-specific overexpression of mTOR (mTOR-Tg mice) to study ischemia-reperfusion (I/R) injury in two animal models: 1) in vivo I/R injury with transient coronary artery ligation and 2) ex vivo I/R injury in Langendorff-perfused hearts with transient global ischemia. At 28 days after I/R, mortality was lower in mTOR-Tg mice than littermate control mice [wild-type (WT) mice]. Echocardiography and MRI demonstrated that global cardiac function in mTOR-Tg mice was preserved, whereas WT mice exhibited significant cardiac dysfunction. Masson's trichrome staining showed that 28 days after I/R, the area of interstitial fibrosis was smaller in mTOR-Tg mice compared with WT mice, suggesting that adverse left ventricular remodeling is inhibited in mTOR-Tg mice. In the ex vivo I/R model, mTOR-Tg hearts demonstrated improved functional recovery compared with WT hearts. Perfusion with Evans blue after ex vivo I/R yielded less staining in mTOR-Tg hearts than WT hearts, indicating that mTOR overexpression inhibited necrosis during I/R injury. Expression of proinflammatory cytokines, including IL-6 and TNF-α, in mTOR-Tg hearts was lower than in WT hearts. Consistent with this, IL-6 in the effluent post-I/R injury was lower in mTOR-Tg hearts than in WT hearts. These findings suggest that cardiac mTOR overexpression in the heart is sufficient to provide substantial cardioprotection against I/R injury and suppress the inflammatory response.
authors.affiliation: Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, 96813, USA.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Aoyagi
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kusakari
authors.forename: Chun-Yang
authors.initials: CY
authors.lastname: Xiao
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Inouye
authors.forename: Masaya
authors.initials: M
authors.lastname: Takahashi
authors.forename: Marielle
authors.initials: M
authors.lastname: Scherrer-Crosbie
authors.forename: Anthony
authors.initials: A
authors.lastname: Rosenzweig
authors.forename: Kenta
authors.initials: K
authors.lastname: Hara
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsui
mesh_terms: D000818:Animals; D001343:Autophagy; D015153:Blotting, Western; D003331:Coronary Vessels / Q000502:physiology; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005355:Fibrosis; D066298:In Vitro Techniques; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D008026:Ligation; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D009336:Necrosis; D010477:Perfusion; D060888:Real-Time Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D014463:Ultrasonography
chemical_list: D004247:DNA; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases