HMG-CoA Reductase Inhibitors Inhibit Inducible Nitric Oxide Synthase Gene Expression in Macrophages

Abstract

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, statins, are potent inhibitors of cholesterol synthesis and have wide therapeutic use in cardiovascular diseases. Recent evidence, however, suggests that the beneficial effects of statins may extend beyond their action on serum cholesterol levels. In this study, we investigated the effects of lovastatin, pravastatin, atorvastatin and fluvastatin on macrophage formation of nitric oxide (NO) in murine RAW 264.7 cells. Stimulation of macrophages with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) resulted in inducible NO synthase (iNOS) expression, which was accompanied by a large amount of NO formation. At concentrations of 0.1–30 µM, statins can inhibit stimuli-induced NO formation and iNOS induction to different extents. This inhibition occurs at the transcriptional level, and displays potency in the order of lovastatin > atorvastatin > fluvastatin >> pravastatin. We found that LPS-induced IĸB kinase and nuclear factor-ĸB (NF-ĸB) activation, as well as IFN-γ-induced signal transducer and activator of transcription 1 (STAT1) phosphorylation, were reduced by lovastatin. Moreover, inhibition by lovastatin of NO production and ĸB activation was reversed by mevalonate, geranylgeranyl pyrophosphate and farnesyl pyrophosphate. All these results suggest that inhibition of iNOS gene expression by statins can be attributed to interference with protein isoprenylation, which mediates both NF-ĸB and STAT1 activation in the upstream signaling pathways for iNOS gene transcription.

Long-chain fatty alcohols from pomace olive oil modulate the release of proinflammatory mediators

“…For this reason, it has been hypothesized that LCFAs might mimic the effect of statins on iNOS expression [35]. Should this hypothesis turns out to be correct, LCFAs might modulate NO release by acting on iNOS transcription, probably by inactivating the nuclear transcription factor NFκB, just as statins do [36].…”

Effect of resveratrol on peritoneal macrophages in rats with severe acute pancreatitis

“…When macrophages received infl ammatory stimulation by SAP, such as TNF-a and IL-6, the NF-kB in cytoplasm would be activated and then translocated to nucleus. As an important factor of delivering intracellular signals, NF-kB modulates the transcription of many infl ammatory mediators and furthermore, results in substantive release of infl ammatory mediators in SAP, including TNF-a , IL-1 and iNOS [28][29][30]. In previous studies, the functions of monocytes in circulation and macrophages in organs has been studied extensively.…”

Gamma interferon: a central mediator in atherosclerosis

“…The in vitro effects of statins on IFN-g mediated infl ammatory processes associated with plaque progression will be considered (Table 4) to exemplify how statin anti-infl ammatory effects in vivo could occur in part through multiple interventions along the IFN-g axis. Statins have been demonstrated to inhibit both IFN-g production in T cells by shifting the T cell population towards the Th2 pathway [183][184][185] as well as inhibiting IFN-g effects on macrophages, endothelial cells and vascular SMC [186][187][188][189][190][191][192][193][194][195][196][197][198]. In general, the in vitro and in vivo effects of statins on IFN-g stimulated cellular changes were dose dependent and vary in potency depending on the specifi c statin.…”

“…In vitro effects of statins on IFN-g activation of macrophages include inhibition of iNOS induction in LPS + IFN-g stimulated RAW 264.7 cells [189,198], neopterin synthesis in human macrophage lines [187], IFN-g induction of CD40 [191,195] and class II but not class I antigen on human macrophages [191], as well as increases in the costimulatory molecules CD40, CD80 and CD86 in primary mouse macrophages [185]. The decreased expression of CD40, CD80, CD86, and class II antigens would be anticipated to mitigate adaptive immunity within the atherosclerotic lesion by inhibiting antigen presentation and subsequent Th1 cell polarization.…”

“…In addition, CD40 ligand induced IL-6, IL-8 and MCP-1 secretion were reduced in these statin treated cells. IFN-g induction of cellular adhesion molecules including ICAM-1 and VCAM-1 was inhibited in Statin 1 Effect Reference A, C, F, S Inhibits IFN-g synthesis in activated T cells [183,185,203] A, L, P, S Inhibits IFN-g induced class II antigen in macrophages, endothelial cells [180,185,191,196] A, L Inhibits IFN-g induced endothelial ICAM-1 and VCAM-1 [186,192] C, F Inhibits IFN-g induced endothelial RANTES, MCP-1 [194] F, L Inhibits iNOS induction and Stat1 phosphorylation, increases SOCS-3 in macrophages [189,198] C, F Increases iNOS, tetrahydrobiopterin, GTP cyclohydrolase I in IFN-g induced SMC [201,202] A, C, P, L, S, Inhibits IFN-g induced CD40 in endothelial, SMC, macrophages, reduces CD40L induced IL-6, 8, MCP-1 [192,193] A I nhibits IFN-g induced CD40, 80, 86 in mouse and neopterin synthesis in human macrophages [185,187] the transformed human endothelial cell line ECV304 [186] and in primary human endothelial cells [192] respectively. Lovastatin treatment of the ECV304 cells did not inhibit tyrosine 701 phosphorylation of Stat1 but did inhibit serine 727 phosphorylation as well as phosphorylation of the ERK kinases on threonine 202 and tyrosine 204 [186].…”