The alteration of protein prenylation induces cardiomyocyte hypertrophy through Rheb-mTORC1 signalling and leads to chronic heart failure.
G protein-regulated cell function is crucial for cardiomyocytes, and any deregulation of its gene expression or protein modification can lead to pathological cardiac hypertrophy. Herein, we report that protein prenylation, a lipidic modification of G proteins that facilitates their association with the cell membrane, might control the process of cardiomyocyte hypertrophy. We found that geranylgeranyl diphosphate synthase (GGPPS), a key enzyme involved in protein prenylation, played a critical role in postnatal heart growth by regulating cardiomyocyte size. Cardiac-specific knockout of GGPPS in mice led to spontaneous cardiac hypertrophy, beginning from week 4, accompanied by the persistent enlargement of cardiomyocytes. This hypertrophic effect occurred by altered prenylation of G proteins. Evaluation of the prenylation, membrane association and hydrophobicity showed that Rheb was hyperactivated and increased mTORC1 signalling pathway after GGPPS deletion. Protein farnesylation or mTORC1 inhibition blocked GGPPS knockdown-induced mTORC1 activation and suppressed the larger neonatal rat ventricle myocyte size and cardiomyocyte hypertrophy in vivo, demonstrating a central role of the FPP-Rheb-mTORC1 axis for GGPPS deficiency-induced cardiomyocyte hypertrophy. The sustained cardiomyocyte hypertrophy progressively provoked cardiac decompensation and dysfunction, ultimately causing heart failure and adult death. Importantly, GGPPS was down-regulated in the hypertrophic hearts of mice subjected to transverse aortic constriction (TAC) and in failing human hearts. Moreover, HPLC-MS/MS detection revealed that the myocardial farnesyl diphosphate (FPP):geranylgeranyl diphosphate (GGPP) ratio was enhanced after pressure overload. Our observations conclude that the alteration of protein prenylation promotes cardiomyocyte hypertrophic growth, which acts as a potential cause for pathogenesis of heart failure and may provide a new molecular target for hypertrophic heart disease clinical therapy.
Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Centre and Medical School of Nanjing University, National Resource Centre for Mutant Mice, Nanjing, People's Republic of China.
Na
N
Xu
Shan
S
Guan
Zhong
Z
Chen
Yang
Y
Yu
Jun
J
Xie
Fei-Yan
FY
Pan
Ning-Wei
NW
Zhao
Li
L
Liu
Zhong-Zhou
ZZ
Yang
Xiang
X
Gao
Biao
B
Xu
Chao-Jun
CJ
Li
D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D004195:Disease Models, Animal; D018450:Disease Progression; D051231:Farnesyltranstransferase / Q000172:deficiency* / Q000235:genetics; D005260:Female; D006333:Heart Failure / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects; D034622:RNA Interference; D000076205:Ras Homolog Enriched in Brain Protein; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D016277:Ventricular Function, Left
D046912:Multiprotein Complexes; D009479:Neuropeptides; D047428:Protein Kinase Inhibitors; D000076205:Ras Homolog Enriched in Brain Protein; C087693:Rheb protein, rat; D051231:Farnesyltranstransferase; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins; D020123:Sirolimus
GGPPS; Rheb; cardiac hypertrophy; protein prenylation