title: Inhibition of farnesyl pyrophosphate synthase prevents angiotensin II-induced cardiac fibrosis in vitro.
abstract: Farnesyl pyrophosphate synthase (FPPS)-catalysed isoprenoid intermediates are important for the activation of Ras homologue gene family, member A (RhoA) in angiotensin (Ang) II-induced cardiac fibrosis. This study was designed to investigate the specific role of FPPS in the development of cardiac fibrosis. We demonstrated that FPPS expression was elevated in both in-vivo and in-vitro models of Ang II-mediated cardiac fibrosis. FPPS inhibition by zolendronate and FPPS knock-down by a silencing lentivirus decreased the expression of cardiac fibrosis marker genes, including collagen I, collagen III and transforming growth factor (TGF)-β1. FPPS inhibition was reversed by geranylgeraniol (GGOH) and mimicked by RhoA knock-down with siRhoA. The antagonistic effect of GGOH on the zolendronate-mediated modulation of RhoA activation in Ang II-stimulated cardiac fibroblasts was demonstrated by a pull-down assay. Furthermore, FPPS knock-down also prevented RhoA activation by Ang II in vitro. In conclusion, FPPS and RhoA may be part of a signalling pathway that plays an important role in Ang II-induced cardiac fibrosis in vitro.
authors: Department of Cardiology, Sir Run Run Shaw Hospital, Hangzhou, Zhejiang Province, China.
authors: Z
authors: Z
authors: Li
authors: X
authors: X
authors: Bi
authors: M
authors: M
authors: Wang
authors: J
authors: J
authors: Zhang
authors: J
authors: J
authors: Song
authors: X
authors: X
authors: Shen
authors: J
authors: J
authors: Han
authors: G
authors: G
authors: Fu
authors: Y
authors: Y
authors: Ye
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects; D000818:Animals; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced; D015870:Gene Expression; D055786:Gene Knockout Techniques; D051228:Geranyltranstransferase / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D017368:Protein Prenylation; D034622:RNA Interference; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D051228:Geranyltranstransferase; D020742:rhoA GTP-Binding Protein
keywords: RhoA; cardiac fibrosis; farnesyl pyrophosphate synthase