Nephrology Division, Department of Medicine, Federal University of São Paulo, Brazil.
Cytokine. 2012 Oct;60(1):150-6. doi: 10.1016/j.cyto.2012.04.039. Epub 2012 Jun 2.
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.
The differentiated adipocytes were incubated with 10 μM simvastatin or vehicle and TNF-α 10 ng/mL or vehicle were added to treatment media. After 24h of incubation, the media was harvested and the proteins of interest were analyzed by Multiplex method. Gene expression was analyzed by real time-PCR.
The addition of TNF-α 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-α (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).
Our findings suggested that simvastatin counteracted the stimulatory effect of TNF-α 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.
全身性炎症状态，如肥胖和代谢综合征中所见，与促动脉粥样硬化和促血栓形成的脂肪因子的高血浆水平以及脂联素水平降低有关。HMG-CoA 还原酶抑制剂在降低心血管事件方面具有有益作用，主要归因于其降脂作用，最近的研究表明，这些作用可能是由于其抗炎特性。基于辛伐他汀的多效性，我们研究了该药在基础条件和炎症刺激下对成熟脂肪细胞中脂联素、PAI-1 和 MCP-1 的分泌和表达的影响。
分化的脂肪细胞用 10 μM 辛伐他汀或载体孵育，并向处理培养基中加入 10ng/mL TNF-α或载体。孵育 24 小时后，收获培养基，并用多重方法分析感兴趣的蛋白质。通过实时 PCR 分析基因表达。
TNF-α 的添加增加了 MCP-1 和 PAI-1 的表达和分泌。然而，刺激并没有干扰脂联素的分泌，尽管其表达显著降低。我们的数据还表明，辛伐他汀降低了基础条件（770.4±199.9 对 312.7±113.7 和 1.00±0.14 对 0.63±0.13，p<0.05）和炎症条件下（14945±228.7 对 7837.6±847.4 和 24.16±5.49 对 14.97±2.67，p<0.05，p<0.05）MCP-1 的表达和分泌。辛伐他汀还减弱了 TNF-α诱导的 PAI-1 表达和分泌的增加（16898.6±1663.3 对 12922.1±843.9 和 5.19±3.12 对 0.59±0.16，分别 p<0.05），但在基础条件下对 PAI-1 的表达或分泌没有影响。他汀类药物增加了基础条件和炎症刺激下脂联素的表达（1.03±0.08 对 4.0±0.96 和 0.77±0.19 对 2.16±0.23，分别 p<0.05），并增加了该脂肪因子的分泌，但仅在炎症刺激下（5347.7±1789.3 对 7327.3±753.6，p<0.05）。
我们的发现表明，辛伐他汀拮抗了 TNF-α 对 MCP-1、PAI-1 和脂联素分泌和表达的刺激作用，这暗示了在炎症过程中可能具有抗动脉粥样硬化作用；这些多效性作用在 HMG-CoA 还原酶抑制剂中更为明显。
