Inhibition of farnesylpyrophosphate synthase prevents angiotensin II-induced hypertrophic responses in rat neonatal cardiomyocytes: involvement of the RhoA/Rho kinase pathway.
The RhoA/Rho-kinase (ROCK) pathway is involved in angiotensin (Ang) II-induced cardiac hypertrophy. However, it is still unclear whether inhibition of farnesylpyrophosphate (FPP) synthase can attenuate Ang II-induced hypertrophic responses, and whether it involves the RhoA/ROCK pathway. The anti-hypertrophic effects of inhibition of FPP synthase with alendronate in Ang II-cultured neonatal cardiomyocytes were partially reversed by geranylgeranyol (GGOH) and were mimicked by GGTI-286, a geranylgeranyl transferase-I inhibitor, C3 exoenzyme, an inhibitor of Rho, or Y-27632, an inhibitor of ROCK. Pull-down assay showed alendronate reduced-active RhoA by Ang II was also partially antagonized by GGOH. This study revealed that the inhibition of FPP synthase by alendronate reduces RhoA activation by diminishing geranylgeranylation which prevents Ang II-induced hypertrophic responses in neonatal cardiomyocytes.
Ye
Yang
Y
Institute of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, #79 Qing-Chun Road, Hangzhou 310003, PR China. yeyang1222@163.com
Hu
Shen-Jiang
SJ
Li
Liang
L
D019386:Alendronate / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000517:prevention & control; D004122:Dimethylallyltranstransferase / Q000037:antagonists & inhibitors* / Q000502:physiology; D006984:Hypertrophy / Q000517:prevention & control*; D032383:Myocytes, Cardiac; D054876:Prenylation / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000804:Angiotensin II; D004122:Dimethylallyltranstransferase; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D019386:Alendronate