PMID- 15184287
OWN - NLM
STAT- MEDLINE
DCOM- 20041216
LR  - 20240308
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Linking)
VI  - 109
IP  - 24
DP  - 2004 Jun 22
TI  - Inhibition of mTOR signaling with rapamycin regresses established cardiac 
      hypertrophy induced by pressure overload.
PG  - 3050-5
AB  - 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%. METHODS AND 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.
FAU - McMullen, Julie R
AU  - McMullen JR
AD  - Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical 
      Center, 330 Brookline Ave, Boston, Mass 02215, USA. jmcmulle@bidmc.harvard.edu
FAU - Sherwood, Megan C
AU  - Sherwood MC
FAU - Tarnavski, Oleg
AU  - Tarnavski O
FAU - Zhang, Li
AU  - Zhang L
FAU - Dorfman, Adam L
AU  - Dorfman AL
FAU - Shioi, Tetsuo
AU  - Shioi T
FAU - Izumo, Seigo
AU  - Izumo S
LA  - eng
GR  - R01-HL-65742/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20040607
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (Ribosomal Protein S6)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adaptation, Physiological
MH  - Animals
MH  - Aorta
MH  - Aortic Diseases/complications
MH  - Cardiomegaly/*drug therapy/etiology
MH  - Cell Size/drug effects
MH  - Constriction, Pathologic/complications
MH  - Drug Evaluation, Preclinical
MH  - Gene Expression Regulation/drug effects
MH  - Male
MH  - Mice
MH  - Myocytes, Cardiac/pathology
MH  - Organ Size/drug effects
MH  - Phosphorylation
MH  - Protein Kinases/*drug effects/physiology
MH  - Protein Processing, Post-Translational/drug effects
MH  - Ribosomal Protein S6/metabolism
MH  - Sirolimus/pharmacology/*therapeutic use
MH  - Stroke Volume/drug effects
MH  - TOR Serine-Threonine Kinases
EDAT- 2004/06/09 05:00
MHDA- 2004/12/17 09:00
CRDT- 2004/06/09 05:00
PHST- 2004/06/09 05:00 [pubmed]
PHST- 2004/12/17 09:00 [medline]
PHST- 2004/06/09 05:00 [entrez]
AID - 01.CIR.0000130641.08705.45 [pii]
AID - 10.1161/01.CIR.0000130641.08705.45 [doi]
PST - ppublish
SO  - Circulation. 2004 Jun 22;109(24):3050-5. doi: 10.1161/01.CIR.0000130641.08705.45. 
      Epub 2004 Jun 7.