title: Statins inhibit angiotensin II/Smad pathway and related vascular fibrosis, by a TGF-β-independent process.
abstract: We have recently described that in an experimental model of atherosclerosis and in vascular smooth muscle cells (VSMCs) statins increased the activation of the Smad pathway by transforming growth factor-β (TGF-β), leading to an increase in TGF-β-dependent matrix accumulation and plaque stabilization. Angiotensin II (AngII) activates the Smad pathway and contributes to vascular fibrosis, although the in vivo contribution of TGF-β has not been completely elucidated. Our aim was to further investigate the mechanisms involved in AngII-induced Smad activation in the vasculature, and to clarify the beneficial effects of statins on AngII-induced vascular fibrosis. Infusion of AngII into rats for 3 days activates the Smad pathway and increases fibrotic-related factors, independently of TGF-β, in rat aorta. Treatment with atorvastatin or simvastatin inhibited AngII-induced Smad activation and related-fibrosis. In cultured rat VSMCs, direct AngII/Smad pathway activation was mediated by p38 MAPK and ROCK activation. Preincubation of VSMCs with statins inhibited AngII-induced Smad activation at all time points studied (from 20 minutes to 24 hours). All these data show that statins inhibited several AngII-activated intracellular signaling systems, including p38-MAPK and ROCK, which regulates the AngII/Smad pathway and related profibrotic factors and matrix proteins, independently of TGF-β responses. The inhibitory effect of statins on the AngII/Smad pathway could explain, at least in part, their beneficial effects on hypertension-induced vascular damage.
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Rodrigues Díez
authors.forename: Raquel
authors.initials: R
authors.lastname: Rodrigues-Díez
authors.forename: Carolina
authors.initials: C
authors.lastname: Lavoz
authors.forename: Sandra
authors.initials: S
authors.lastname: Rayego-Mateos
authors.forename: Esther
authors.initials: E
authors.lastname: Civantos
authors.forename: Juan
authors.initials: J
authors.lastname: Rodríguez-Vita
authors.forename: Sergio
authors.initials: S
authors.lastname: Mezzano
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
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; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D000069059:Atorvastatin; D015153:Blotting, Western; D002478:Cells, Cultured; D005355:Fibrosis / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology; D051785:Smad Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000069059:Atorvastatin; D019821:Simvastatin; D048051:p38 Mitogen-Activated Protein Kinases