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Am J Physiol Gastrointest Liver Physiol 296: G147-G156, 2009. First published December 4, 2008; doi:10.1152/ajpgi.00462.2007
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LIVER AND BILIARY TRACT

Atorvastatin attenuates angiotensin II-induced inflammatory actions in the liver

Montserrat Moreno,1,* Leandra N. Ramalho,1,* Pau Sancho-Bru,1 Marta Ruiz-Ortega,2 Fernando Ramalho,1 Juan G. Abraldes,1 Jordi Colmenero,1 Marlene Dominguez,1 Jesús Egido,2 Vicente Arroyo,1 Pere Ginès,1 and Ramón Bataller1

1Liver Unit, 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; and 2Vascular and Renal Research Laboratory, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain

Submitted 6 October 2007 ; accepted in final form 21 November 2008

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-β1 (TGF-β1) 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 (10–8M) stimulated cell proliferation, proinflammatory actions (NF-{kappa}B activation, ICAM-1 expression, interleukin-8 secretion) as well as expression of procollagen-{alpha}1(I) and TGF-β1. All of these effects were reduced in the presence of atorvastatin (10–7M). 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.

statins; fibrosis; renin-angiotensin system; hepatic stellate cells


Address for reprint requests and other correspondence: R. Bataller, Liver Unit, Hospital Clínic, Villarroel 170, 08036-Barcelona, Catalonia, Spain (e-mail: bataller{at}clinic.ub.es)






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