The mTOR/p70S6K signal transduction pathway plays a role in cardiac hypertrophy and influences expression of myosin heavy chain genes in vivo.
OBJECTIVE
Rapamycin inhibits p70 S6 kinase (p70(S6K)) activity and hypertrophy of cultured neonatal rat cardiac myocytes. The purpose of the present study was to determine whether rapamycin inhibits left ventricular (LV) hypertrophy in intact rats and whether it alters cardiac gene expression.


METHODS
300 g rats were subjected to aortic constriction (AC) or sham-operation (SH) and studied 2 and 3 days after surgery. Beginning 1 day prior to surgery, rats were injected with rapamycin (1.5 mg/kg, i.p.) or carboxymethylcellulose vehicle (V), yielding 4 groups (SH-V, SH-R, AC-V, AC-R). Total RNA was extracted for determination of mRNA levels by Northern blotting.


RESULTS
LV dry weight/body weight ratios were 0.43 +/- 0.04 (mean +/- SE) for SH-V, 0.46 +/- 0.02 for SH-R, 0.56 +/- 0.02 for AC-V, and 0.53 +/- 0.03 for AC-R. R inhibited cardiac hypertrophy induced by pressure overload (ANOVA; p < 0.05). Rapamycin had no effect on the expression of atrial natriuretic factor mRNA, but increased the levels of beta-myosin heavy chain mRNA 6-fold in hearts of SH-R and AC-R compared to SH-V. Rapamycin also increased the expression of alpha-myosin heavy chain mRNA in SH-R by 3-fold compared with SH-V, but had no effect on the AC-R group.


CONCLUSIONS
The data suggest that an intact mTOR signaling pathway is required for rapid hypertrophic growth of the heart in vivo. Moreover, the data suggest a novel link between the mTOR/p70(S6K) signal transduction pathway and pretranslational control of myosin gene expression in the heart.
Boluyt
Marvin O
MO
Laboratory of Molecular Kinesiology, The University of Michigan, 401 Washtenaw Avenue, Ann Arbor, MI 48109-2214, USA. boluytm@umich.edu
Li
Zhao Bo
ZB
Loyd
Amy M
AM
Scalia
Antony F
AF
Cirrincione
Georgina M
GM
Jackson
Rebecca R
RR
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D015152:Blotting, Northern; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D018995:Myosin Heavy Chains / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D011494:Protein Kinases; C546845:mTOR protein, rat; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D018995:Myosin Heavy Chains; D020123:Sirolimus