TNF-α modulates statin effects on secretion and expression of MCP-1, PAI-1 and adiponectin in 3T3-L1 differentiated adipocytes

Purpose: Systemic inflammatory conditions, as seen in obesity and in the metabolic syndrome, are associated with high plasmatic levels of proatherogenic and prothromboticadipokines and low levels of adiponectin. Inhibitors of HMG-CoA reductase have beneficial effects in reducing cardiovascular events attributed predominantly to its lipid-lowering effects and recent studies suggest that these effects might be due to its anti-inflammatory properties. Based on the pleiotropic properties of simvastatin we studied the effects of this drug on the secretion and expression of adiponectin, PAI-1 and MCP-1 in mature adipocytes under baseline conditions and after an inflammatory stimulation. Materials and methods: The differentiated adipocytes were incubated with 10 mu M simvastatin or vehicle and TNF-alpha 10 ng/mL or vehicle were added to treatment media. After 24 h of incubation, the media was harvested and the proteins of interest were analyzed by Multiplex method. Gene expression was analyzed by real time-PCR. Results: The addition of TNF-alpha increased the expression and secretion of MCP-1 and PAI-1. However, stimulation did not interfere with the secretion of adiponectin, despite having significantly reduced its expression. Our data also demonstrated that simvastatin reduced the expression and secretion of MCP-1, under baseline (770.4 +/- 199.9 vs 312.7 +/- 113.7 and 1.00 +/- 0.14 vs 0.63 +/- 0.13, p <0.05, respectively) and inflammatory conditions (14945 +/- 228.7 vs 7837.6 +/- 847.4 and 24.16 +/- 5.49 vs 14.97 +/- 2.67, p < 0.05, p < 0.05, respectively). Simvastatin also attenuated the increase in expression and secretion of PAI-1 induced by TNF-alpha (16898.6 +/- 1663.3 vs 12922.1 +/- 843.9 and 5.19 +/- 3.12 vs 0.59 +/- 0.16, respectively p < 0.05), but under baseline conditions had no effect on the expression or secretion of PAI-1. The statin increased the expression of adiponectin under baseline conditions and inflammatory stimulation (1.03 +/- 0.08 vs 4.0 +/- 0.96 and 0.77 +/- 0.19 vs 2.16 +/- 0.23, respectively, p < 0.05) and also increased the secretion of this adipokine. but only with the inflammatory stimulus (5347.7 1789.3 vs 7327.3 +/- 753.6, p <0.05). Conclusions: Our findings suggested that simvastatin counteracted the stimulatory effect of TNF-alpha on secretion and expression of MCP-1, PAI-1 and adiponectin, implying a potential anti-atherogenic effect during the inflammatory process; these pleitropic effects were more pronounced with HMG-CoA reductase inhibitor. (C) 2012 Elsevier Ltd. All rights reserved.