Rheb activates protein synthesis and growth in adult rat ventricular cardiomyocytes.
The mammalian target of rapamycin complex 1 (mTORC1), a key regulator of protein synthesis, growth and proliferation in mammalian cells, is implicated in the development of cardiac hypertrophy. Ras homolog enriched in brain (Rheb) positively regulates mTORC1. We have studied whether Rheb is sufficient to activate mTOR signaling and promote protein synthesis and cardiac hypertrophy in adult rat ventricular cardiomyocytes (ARVC). Rheb was overexpressed via an adenoviral vector in isolated ARVC. Overexpression of Rheb in ARVC activated mTORC1 signaling, several components of the translational machinery and stimulated protein synthesis. Our direct visualization approach to determine ARVC size revealed that overexpression of Rheb also induced cell growth and indeed did so to similar extent to the hypertrophic agent, phenylephrine (PE). Despite potent activation of mTORC1 signaling, overexpression of Rheb did not induce expression of the cardiac hypertrophic marker mRNAs for brain natriuretic peptide and atrial natriuretic factor, while PE treatment did markedly increase their expression. All the effects of Rheb were blocked by rapamycin, confirming their dependence on mTORC1 signaling. Our findings reveal that Rheb itself can activate both protein synthesis and cell growth in ARVC and demonstrate the key role played by mTORC1 in the growth of cardiomyocytes.
Wang
Yanni
Y
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
Huang
Brandon P H
BP
Luciani
Dan S
DS
Wang
Xuemin
X
Johnson
James D
JD
Proud
Christopher G
CG
D000256:Adenoviridae; D000818:Animals; D000900:Anti-Bacterial Agents; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D005822:Genetic Vectors; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D008297:Male; D020559:Monomeric GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis / Q000235:genetics; D009479:Neuropeptides / Q000096:biosynthesis* / Q000235:genetics; D010656:Phenylephrine / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology*; D011494:Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D000076205:Ras Homolog Enriched in Brain Protein; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D000900:Anti-Bacterial Agents; D015415:Biomarkers; D002316:Cardiotonic Agents; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C087693:Rheb protein, rat; D020097:Natriuretic Peptide, Brain; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins; D020123:Sirolimus