title: Inhibition of farnesyl pyrophosphate synthase attenuates angiotensin II-induced fibrotic responses in vascular smooth muscle cells.
abstract: Through the regulation of the RhoA/Rho kinase (ROCK) pathway, angiotensin II (Ang II)-induced fibrotic responses contribute to vascular remodeling. Farnesyl pyrophosphate synthase (FPPS) plays an important role in cardiovascular remodeling through the modulation of the above-mentioned pathway. However, the role of FPPS in Ang II-induced fibrotic responses and the related molecular mechanisms have not yet been elucidated. In the present study, vascular smooth muscle cells (VSMCs) from Sprague-Dawley (SD) rats were stimulated with Ang II. Cell proliferation was measusred usin the cell counting kit-8 (CCK-8). The levels of connective tissue growth factor (CTGF), FPPS, and those of phosphorylated and total extracellular signal-regulated kinase (ERK)1/2, p38 and c-Jun N-terminal kinase (JNK) were determined by western blot analysis. RhoA activity was determined using a pull-down assay. The results revealed that stimulation with Ang II enhanced cell proliferation, and increased the protein expression levels of FPPS and CTGF in the VSMCs. The inhibition of FPPS with ibandronate sodium attenuated the Ang II-induced increase in cell proliferation, CTGF expresison and RhoA activity; these effects were partially reversed by treatment with geranylgeraniol and were mimicked by GGTI-286. Furthermore, both SB203580 (a specific inhibitor of p38) and SP600125 (JNK1, JNK2 and JNK3 inhibitor) diminished the Ang II-induced production of CTGF; however, the inhibition of FPPS reduced the Ang II-induced activation of p38 mitogen-activated protein kinase (MAPK) and JNK. In conclusion, our data indicate that FPPS may play an important role in Ang II-induced fibrotic responses in VSMCs, and the underlying mechanisms at least partly involve the modulation of RhoA activity, and the p38 and JNK pathways.
authors.affiliation: Department of Cardiology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, P.R. China.
authors.forename: Chang-Qing
authors.initials: CQ
authors.lastname: Du
authors.affiliation: Department of Cardiology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, P.R. China.
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, P.R. China.
authors.forename: Guang-Zhong
authors.initials: GZ
authors.lastname: Zeng
authors.affiliation: Department of Cardiology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, P.R. China.
authors.forename: Hong-Feng
authors.initials: HF
authors.lastname: Jin
authors.affiliation: Department of Cardiology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, P.R. China.
authors.forename: Li-Jiang
authors.initials: LJ
authors.lastname: Tang
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C526316:CCN2 protein, rat; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D051228:Geranyltranstransferase; D048049:Extracellular Signal-Regulated MAP Kinases; D020742:rhoA GTP-Binding Protein