title: HMG-CoA reductase inhibitors decrease angiotensin II-induced vascular fibrosis: role of RhoA/ROCK and MAPK pathways.
abstract: 3-Hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) present beneficial effects in cardiovascular diseases. Angiotensin II (Ang II) contributes to cardiovascular damage through the production of profibrotic factors, such as connective tissue growth factor (CTGF). Our aim was to investigate whether HMG-CoA reductase inhibitors could modulate Ang II responses, evaluating CTGF expression and the mechanisms underlying this process. In cultured vascular smooth muscle cells (VSMCs) atorvastatin and simvastatin inhibited Ang II-induced CTGF production. The inhibitory effect of statins on CTGF upregulation was reversed by mevalonate and geranylgeranylpyrophosphate, suggesting that RhoA inhibition could be involved in this process. In VSMCs, statins inhibited Ang II-induced Rho membrane localization and activation. In these cells Ang II regulated CTGF via RhoA/Rho kinase activation, as shown by inhibition of Rho with C3 exoenzyme, RhoA dominant-negative overexpression, and Rho kinase inhibition. Furthermore, activation of p38MAPK and JNK, and redox process were also involved in Ang II-mediated CTGF upregulation, and were downregulated by statins. In rats infused with Ang II (100 ng/kg per minute) for 2 weeks, treatment with atorvastatin (5 mg/kg per day) diminished aortic CTGF and Rho activation without blood pressure modification. Rho kinase inhibition decreased CTGF upregulation in rat aorta, mimicking statin effect. CTGF is a vascular fibrosis mediator. Statins diminished extracellular matrix (ECM) overexpression caused by Ang II in vivo and in vitro. In summary, HMG-CoA reductase inhibitors inhibit several intracellular signaling systems activated by Ang II (RhoA/Rho kinase and MAPK pathways and redox process) involved in the regulation of CTGF. Our results may explain, at least in part, some beneficial effects of statins in cardiovascular diseases.
authors.affiliation: Vascular and Renal Research Laboratory, Cellular Biology in Renal Diseases Laboratory, Fundación Jiménez Diaz, Universidad Autónoma Madrid, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Rupérez
authors.forename: Raquel
authors.initials: R
authors.lastname: Rodrigues-Díez
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Blanco-Colio
authors.forename: Elsa
authors.initials: E
authors.lastname: Sánchez-López
authors.forename: Juan
authors.initials: J
authors.lastname: Rodríguez-Vita
authors.forename: Vanesa
authors.initials: V
authors.lastname: Esteban
authors.forename: Gisselle
authors.initials: G
authors.lastname: Carvajal
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Plaza
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D004195:Disease Models, Animal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D017874:Immediate-Early Proteins / Q000187:drug effects / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: C526316:CCN2 protein, rat; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D020928:Mitogen-Activated Protein Kinases; D020741:rho GTP-Binding Proteins