Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload.
BACKGROUND
Rapamycin is a specific inhibitor of the mammalian target of rapamycin (mTOR). We recently reported that administration of rapamycin before exposure to ascending aortic constriction significantly attenuated the load-induced increase in heart weight by approximately 70%.


RESULTS
To examine whether rapamycin can regress established cardiac hypertrophy, mice were subjected to pressure overload (ascending aortic constriction) for 1 week, echocardiography was performed to verify an increase in ventricular wall thickness, and mice were given rapamycin (2 mg x kg(-1) x d(-1)) for 1 week. After 1 week of pressure overload (before treatment), 2 distinct groups of animals became apparent: (1) mice with compensated cardiac hypertrophy (normal function) and (2) mice with decompensated hypertrophy (dilated with depressed function). Rapamycin regressed the pressure overload-induced increase in heart weight/body weight (HW/BW) ratio by 68% in mice with compensated hypertrophy and 41% in mice with decompensated hypertrophy. Rapamycin improved left ventricular end-systolic dimensions, fractional shortening, and ejection fraction in mice with decompensated cardiac hypertrophy. Rapamycin also altered the expression of some fetal genes, reversing, in part, changes in alpha-myosin heavy chain and sarcoplasmic reticulum Ca2+ ATPase.


CONCLUSIONS
Rapamycin may be a therapeutic tool to regress established cardiac hypertrophy and improve cardiac function.
McMullen
Julie R
JR
Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, Mass 02215, USA. jmcmulle@bidmc.harvard.edu
Sherwood
Megan C
MC
Tarnavski
Oleg
O
Zhang
Li
L
Dorfman
Adam L
AL
Shioi
Tetsuo
T
Izumo
Seigo
S
D000222:Adaptation, Physiological; D000818:Animals; D001011:Aorta; D001018:Aortic Diseases / Q000150:complications; D006332:Cardiomegaly / Q000188:drug therapy* / Q000209:etiology; D048429:Cell Size / Q000187:drug effects; D003251:Constriction, Pathologic / Q000150:complications; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation; D011494:Protein Kinases / Q000187:drug effects* / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D038601:Ribosomal Protein S6 / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D013318:Stroke Volume / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases
D038601:Ribosomal Protein S6; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus