Atorvastatin attenuates angiotensin II-induced inflammatory actions in the liver.
Statins exert beneficial effects in chronically damaged tissues. Angiotensin II (ANG II) participates in liver fibrogenesis by inducing oxidative stress, inflammation, and transforming growth factor-beta1 (TGF-beta1) expression. We investigate whether atorvastatin modulates ANG II-induced pathogenic effects in the liver. Male Wistar rats were infused with saline or ANG II (100 ng kg(-1) min(-1)) for 4 wk through a subcutaneous osmotic pump. Rats received either vehicle or atorvastatin (5 mg kg(-1) day(-1)) by gavage. ANG II infusion resulted in infiltration of inflammatory cells (CD43 immunostaining), oxidative stress (4-hydroxynonenal), hepatic stellate cells (HSC) activation (smooth muscle alpha-actin), increased intercellular adhesion molecule (ICAM-1), and interleukin-6 hepatic gene expression (quantitative PCR). These effects were markedly blunted in rats receiving atorvastatin. The beneficial effects of atorvastatin were confirmed in an additional model of acute liver injury (carbon tetrachloride administration). We next explored whether the beneficial effects of atorvastatin on ANG II-induced actions are also reproduced at the cellular level. We studied HSC, a cell type with inflammatory and fibrogenic properties. ANG II (10(-8)M) stimulated cell proliferation, proinflammatory actions (NF-kappaB activation, ICAM-1 expression, interleukin-8 secretion) as well as expression of procollagen-alpha(1(I)) and TGF-beta1. All of these effects were reduced in the presence of atorvastatin (10(-7)M). These results indicate that atorvastatin attenuates the pathogenic events induced by ANG II in the liver both in vivo and in vitro. Therefore, statins could have beneficial effects in conditions characterized by hepatic inflammation.
Moreno
Montserrat
M
Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica Esther Koplowitz, Barcelona, Catalonia, Spain.
Ramalho
Leandra N
LN
Sancho-Bru
Pau
P
Ruiz-Ortega
Marta
M
Ramalho
Fernando
F
Abraldes
Juan G
JG
Colmenero
Jordi
J
Dominguez
Marlene
M
Egido
Jesús
J
Arroyo
Vicente
V
Ginès
Pere
P
Bataller
Ramón
R
D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000069059:Atorvastatin; D002251:Carbon Tetrachloride; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004195:Disease Models, Animal; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D015918:Infusion Pumps, Implantable; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D015850:Interleukin-6; D011758:Pyrroles; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; D000069059:Atorvastatin; D002251:Carbon Tetrachloride