title: Rapamycin attenuates load-induced cardiac hypertrophy in mice.
abstract: BACKGROUND
  Cardiac hypertrophy, or an increase in heart size, is an important risk factor for cardiac morbidity and mortality. The mammalian target of rapamycin (mTOR) is a component of the insulin-phosphoinositide 3-kinase pathway, which is known to play a critical role in the determination of cell, organ, and body size.
  
  
  RESULTS
  To examine the role of mTOR in load-induced cardiac hypertrophy, we administered rapamycin, a specific inhibitor of mTOR, to mice with ascending aortic constriction. Activity of p70 ribosomal S6 kinase 1 (S6K1), an effector of mTOR, was increased by 3.8-fold in the aortic-constricted heart. Pretreatment of mice with 2 mg. kg-1. d-1 of rapamycin completely suppressed S6K1 activation and S6 phosphorylation in response to pressure overload. The heart weight/tibial length ratio of vehicle-treated aortic-banded mice was increased by 34.4+/-3.6% compared with vehicle-treated sham-operated mice. Rapamycin suppressed the load-induced increase in heart weight by 67%. Attenuation of cardiac hypertrophy by rapamycin was associated with attenuation of the increase in myocyte cell size induced by aortic constriction. Rapamycin did not cause loss of body weight, lethality, or left ventricular dysfunction.
  
  
  CONCLUSIONS
  mTOR or its target(s) seems to play an important role in load-induced cardiac hypertrophy. Because systemic administration of rapamycin has been used successfully for the treatment of transplant rejection in clinical practice, it may be a useful therapeutic modality to suppress cardiac hypertrophy in patients.
authors.affiliation: Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, Mass 02215, USA.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shioi
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
authors.forename: Oleg
authors.initials: O
authors.lastname: Tarnavski
authors.forename: Kimber
authors.initials: K
authors.lastname: Converso
authors.forename: Megan C
authors.initials: MC
authors.lastname: Sherwood
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Manning
authors.forename: Seigo
authors.initials: S
authors.lastname: Izumo
mesh_terms: D000818:Animals; D001011:Aorta; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003250:Constriction; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D009929:Organ Size; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D038601:Ribosomal Protein S6 / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D038601:Ribosomal Protein S6; D011494:Protein Kinases; C546843:mTOR protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D020123:Sirolimus