title: Atorvastatin prevents angiotensin II-induced vascular remodeling and oxidative stress.
abstract: Angiotensin II (Ang II) modulates vasomotor tone, cell growth, and extracellular matrix deposition. This study analyzed the effect of atorvastatin in the possible alterations induced by Ang II on structure and mechanics of mesenteric resistance arteries and the signaling mechanisms involved. Wistar rats were infused with Ang II (100 ng/kg per day, SC minipumps, 2 weeks) with or without atorvastatin (5 mg/kg per day). Ang II increased blood pressure and plasmatic malondialdehyde levels. Compared with controls, mesenteric resistance arteries from Ang II-treated rats showed the following: (1) decreased lumen diameter; (2) increased wall/lumen; (3) decreased number of adventitial, smooth muscle, and endothelial cells; (4) increased stiffness; (5) increased collagen deposition; and (6) diminished fenestrae area and number in the internal elastic lamina. Atorvastatin did not alter blood pressure but reversed all of the structural and mechanical alterations of mesenteric arteries, including collagen and elastin alterations. In mesenteric resistance arteries, Ang II increased vascular O(2)(.-) production and diminished endothelial NO synthase and CuZn/superoxide dismutase but did not modify extracellular-superoxide dismutase expression. Atorvastatin improved plasmatic and vascular oxidative stress, normalized endothelial NO synthase and CuZn/superoxide dismutase expression, and increased extracellular-superoxide dismutase expression, showing antioxidant properties. Atorvastatin also diminished extracellular signal-regulated kinase 1/2 activation caused by Ang II in these vessels, indicating an interaction with Ang II-induced intracellular responses. In vascular smooth muscle cells, collagen type I release mediated by Ang II was reduced by different antioxidants and statins. Moreover, atorvastatin downregulated the Ang II-induced NADPH oxidase subunit, Nox1, expression. Our results suggest that statins might exert beneficial effects on hypertension-induced vascular remodeling by improving vascular structure, extracellular matrix alterations, and vascular stiffness. These effects might be mediated by their antioxidant properties.
authors.affiliation: Departmento de Farmacología, Universidad Autónoma de Madrid, Spain. ana.briones@uam.es
authors.forename: Ana M
authors.initials: AM
authors.lastname: Briones
authors.forename: Natalia
authors.initials: N
authors.lastname: Rodríguez-Criado
authors.forename: Raquel
authors.initials: R
authors.lastname: Hernanz
authors.forename: Ana B
authors.initials: AB
authors.lastname: García-Redondo
authors.forename: Raul R
authors.initials: RR
authors.lastname: Rodrigues-Díez
authors.forename: María J
authors.initials: MJ
authors.lastname: Alonso
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.forename: Mercedes
authors.initials: M
authors.lastname: Salaices
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000069059:Atorvastatin; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004548:Elasticity / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008315:Malondialdehyde / Q000097:blood; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018613:Microscopy, Confocal; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D014662:Vasoconstrictor Agents; D013481:Superoxides; D000804:Angiotensin II; D008315:Malondialdehyde; D003094:Collagen; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D020928:Mitogen-Activated Protein Kinases