Atherosclerosis has been considered an inflammatory disease. Inflammatory mediators such as TNF-α, interleukin-1 and C-reactiv protein paly an important role in atheogenesis. Resistin could stimulate expression of TNF-α, interleukin-1, 6 and 12 in cultured macrophages [3, 11]. We have previously demonstrated a remarkable induction of resistin protein level even after stimulation with low level of TNF-α in vascular smooth muscle cells . In this study, we further demonstrated that resistin protein and mRNA levels can be induced by TNF-α in cultured human macrophages. Macrophages and vascular smooth muscle cells are important components in the atheroma. These findings indicate that resistin is a promising target for controlling atherosclerotic disease.
Biomarkers that integrate metabolic and inflammatory signals are attractive candidates for defining risk of atherosclerotic cardiovascular disease . Hyperresistinemia impairs glucose tolerance and induces hepatic insulin resistance in rodents , whereas mice deficient in resistin are protected from obesity associated insulin resistance . In this study, we also demonstrated that recombinant resistin protein and TNF-α reduced glucose uptake in human macrophages and atorvastatin reversed the abnormal glucose uptake induced by resistin and TNF-α. Resistin may represent a novel link between metabolic signals, inflammation, and atherosclerosis .
Norata et al. have reported that plasma resistin levels are increased in the presence of metabolic syndrome and are associated with increased cardiovascular risk . Lubos et al. have also reported that resistin levels are elevated in patients with acute coronary syndrome and might play a role as a diagnostic marker . Recently, resistin was found to induce lipolysis and re-esterification of triacylglycerol stores and increase cholesteryl ester deposition in human macrophages . Therefore, resistin contributes macrophage form cell formation. Statins have been shown to reduce lipid lowering effects as well as pleiotropic properties. Although statin cannot alter resistin levels in patients with type 2 diabetic and in healthy men [20–22], statins have been shown to reduce resistin expression in human monocytes and adipocytes [10, 23]. These data implicate that statins may control inflammatory responses by inhibiting resistin expression.
Indeed, our study demonstrated that TNF-α induced resistin protein and mRNA expression in human macrophages and atorvastatin decreased TNF-α-induced resistin expression in a dose-dependent manner. The induction of resistin protein by TNF-α was largely mediated by JNK kinase pathway because the specific and potent inhibitors of an upstream JNK kinase, SP600125, inhibited the induction of resistin protein. Atorvastatin also inhibited the phosphorylation of rac induced by TNF-α. In this study, we demonstrated that TNF-α stimulation of AP-1-DNA binding activity required at least phosphorylation of the JNK since JNK inhibitor abolished the AP-1 binding activity. Atorvastatin also attenuated the AP-1 binding activity induced by TNF-α. The promoter activity of wild resistin promoter after TNF-α was significantly higher than that of AP-1 mutant resistin promoter. This finding indicates that TNF-α regulates resistin in human macrophages at transcriptional level and that AP-1 binding sites in the resistin promoter is essential for the transcriptional regulation. Taken together, our results indicate that TNF-α may increase the AP-1 transcriptional activity in macrophages. Resistin induced by TNF-α was largely though JNK, rac and resistin promoter pathways and atorvastatin could inhibit resistin expression through inhibition of rac phosphorylation, reduced AP-1 binding activity and resistin promoter activity.
In our study, we demonstrated that inhibition of the TNF-α-induced resistin expression by atorvastatin was independent of HMG-CoA reductase. Downregulation of resistin expression induced by CRP by simvastatin was independent of HMG-CoA reductase . Rac pathway mediates the signal trasndcution by isoprenoid intermediates, such as farnesylpyrophosphate and geranylgeranyl-pyrophosphate. In this study, we did not test the effect of isoprenoid intermediate on inhibition of TNF-α-induced resistin expression by atorvastatin. We demonstrated that TNF-α and mevalonate induce resisitn at the similar level. However, atorvastatin only blocks TNF-α but not mevalonate induced resistin. TNF-α but not mevalonate induces rac phosphorylation in cultured macrophages. JNK specific inhibitor S600125 blocked both TNF-α and mevalonate induced resistin expression. This data suggests that mevalonate plays a proinflammatory role and atorvastatin attenuates resistin expression induced by TNF-α is independent of HMG-CoA reductase but through inhibition of Rac and JNK pathway.
In conclusion, our study confirmed previous findings that TNF-α could induce resistin expression in human macrophages and atorvastatin could inhibit the resistin expression induced by TNF-α. The inhibitory effect of atorvastatin on TNF-α-induced resistin expression was mediated by rac and resistin promoter. Our findings provide another evidence of pleiotropic effect of statin. Statin therapy may become another therapeutic strategy for controlling resistin-associated pathologic cardiovascular disease in humans.