title: Alendronate prevents angiotensin II-induced collagen I production through geranylgeranylation-dependent RhoA/Rho kinase activation in cardiac fibroblasts.
abstract: 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.
authors.affiliation: Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China. Electronic address: yeyang1222@163.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China. Electronic address: lvxuezju@126.com.
authors.forename: Xue
authors.initials: X
authors.lastname: Lv
authors.affiliation: Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.
authors.forename: Mei-hui
authors.initials: MH
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.
authors.forename: Shi-quan
authors.initials: SQ
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.
authors.forename: Chen-yang
authors.initials: CY
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.
authors.forename: Guo-sheng
authors.initials: GS
authors.lastname: Fu
mesh_terms: D019386:Alendronate / Q000494:pharmacology*; D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis*; D003864:Depression, Chemical; D004224:Diterpenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis / Q000188:drug therapy; D008297:Male; D058990:Molecular Targeted Therapy; D009206:Myocardium / Q000166:cytology* / Q000473:pathology; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism* / Q000502:physiology*
chemical_list: D024042:Collagen Type I; D004224:Diterpenes; D000804:Angiotensin II; C017338:geranylgeraniol; D054460:rho-Associated Kinases; D019386:Alendronate
keywords: Alendronate; Collagen I; Geranylgeranylation; Rho kinase; RhoA