Atorvastatin attenuates angiotensin II-induced inflammatory actions in the liver

Abstract

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.

Myocardial fibrosis in response to Angiotensin II is preceded by the recruitment of mesenchymal progenitor cells

“…20,39,40 Furthermore, others have shown that AngII exposure leads to the recruitment of fibrocytes into renal tissue in a model of kidney fibrosis. 40 Importantly, fibrocytes can be recruited in response to SDF-1a gradients.…”

Transforming growth factor beta1 (TGFbeta1) in physiology and pathology

“…TGFb1 synthesis is stimulated by physical, mechanical, and biochemical factors [12]. Increased TGFb1 activity has been observed in response to angiotensin II [13][14][15][16], LDL, glucose, thromboxane A2. Natural inhibitors of TGFb1 are follistatin, decorin, and a2-macroglobulin [12].…”

“…In chronic processes, the excessive and persistent production of TGFb1 occurs which leads to progressive fibrosis [7,47,48,68]. Synthesis and profibrogenic action of TGFb1 are intensified by angiotensin II which is therefore another mediator of ECM production in the liver [13,[14][15][16]. TGFb1 is one of the key mediators of fibrogenesis.…”

Oral Formulation of Angiotensin-(1–7) Improves Lipid Metabolism and Prevents High-Fat Diet–Induced Hepatic Steatosis and Inflammation in Mice

“…40,41 Several data suggested the involvement of TNF-α and IL-6 in the metabolic syndrome and progression of NAFLD, perhaps, in part through increased mitochondrial dysfunction and 44 Ang II-infused rats presented increased IL-6 expression in the liver with associated increase in monocyte recruitment and overall inflammation. 45 A recent study showed that Ang-(1-7) was able to reduce inflammatory markers in rats with diabetic nephropathy. 46 These data were supported by a study that revealed different molecular approaches for Ang-(1-7)-modulated inflammatory responses in mouse peritoneal macrophages, decreasing IL-6 and TNF-α.…”