Alendronate prevents angiotensin II-induced collagen i production through geranylgeranylation-dependent RhoA/Rho kinase activation in cardiac fibroblasts

Collagen i is the main component of extracellular matrix in cardiac fibrosis. our previous studies have reported inhibition of farnesylpyrophosphate synthase prevents angiotensin ii-induced cardiac fibrosis,while the exact molecular mechanism was still unclear. this paper was designed to investigate the effect of alendronate,a farnesylpyrophosphate synthase inhibitor,on regulating angiotensin ii-induced collagen i expression in cultured cardiac fibroblasts and to explore the underlying mechanism. by measuring the mrna and protein levels of collagen i,we found that alendronate prevented angiotensin ii-induced collagen i production in a dose-dependent manner. the inhibitory effect on collagen i expression was reversed by geranylgeraniol,and mimicked by inhibitors of rhoa/rho kinase pathway including c3 exoenzyme and ggti-286. thus we suggested geranylgeranylation-dependent rhoa/rho kinase activation was involved in alendronate-mediated anti-collagen i synthetic effect. furthermore,we accessed the activation status of rhoa in alendronate-,geranylgeraniol- and ggti-286-treated cardiac fibroblasts and gave an indirect evidence for rhoa activation via geranylgeranylation. then we came to the conclusion that in cardiac fibroblasts,alendronate could protect against angiotensin ii-induced collagen i synthesis through inhibition of geranylgeranylation and inactivation of rhoa/rho kinase signaling. targeting geranylgeranylation and rhoa/rho kinase signaling will hopefully serve as therapeutic strategies to reduce fibrosis in heart remodeling. © 2015 the authors.