OBJECTIVE Calcification of atherosclerotic plaque is traditionally associated with increased cardiovascular event risk; however, recent studies have found increased calcium density to be associated with more stable disease. 3-hydroxy-3-methylglutaryl coenzymeA reductase inhibitors or statins reduce cardiovascular events. Invasive clinical studies have found that statins alter both the lipid and calcium composition of plaque but the molecular mechanisms of statin-mediated effects on plaque calcium composition remain unclear. We recently defined a macrophage Rac (Ras-related C3 botulinum toxin substrate)-IL-1β (interleukin-1 beta) signaling axis to be a key mechanism in promoting atherosclerotic calcification and sought to define the impact of statin therapy on this pathway. Approach and Results: Here, we demonstrate that statin therapy is independently associated with elevated coronary calcification in a high-risk patient population and that statins disrupt the complex between Rac1 and its inhibitor RhoGDI (Rho GDP-dissociation inhibitor), leading to increased active (GTP bound) Rac1 in primary monocytes/macrophages. Rac1 activation is prevented by rescue with the isoprenyl precursor geranylgeranyl diphosphate. Statin-treated macrophages exhibit increased activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), increased IL-1β mRNA, and increased Rac1-dependent IL-1β protein secretion in response to inflammasome stimulation. Using an animal model of calcific atherosclerosis, inclusion of statin in the atherogenic diet led to a myeloid Rac1-dependent increase in atherosclerotic calcification, which was associated with increased serum IL-1β expression, increased plaque Rac1 activation, and increased plaque expression of the osteogenic markers, alkaline phosphatase and RUNX2 (Runt-related transcription factor 2). CONCLUSIONS Statins are capable of increasing atherosclerotic calcification through disinhibition of a macrophage Rac1-IL-1β signaling axis.

中文翻译：

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他汀类药物破坏巨噬细胞 Rac1 调节，导致动脉粥样硬化斑块钙化增加。

目的 动脉粥样硬化斑块的钙化历来与心血管事件风险增加有关。然而，最近的研究发现钙密度增加与疾病更稳定有关。3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂或他汀类药物可减少心血管事件。侵入性临床研究发现，他汀类药物会改变斑块的脂质和钙成分，但他汀类药物介导的斑块钙成分影响的分子机制仍不清楚。我们最近将巨噬细胞 Rac（Ras 相关 C3 肉毒杆菌毒素底物）-IL-1β（白介素-1 β）信号轴定义为促进动脉粥样硬化钙化的关键机制，并试图确定他汀类药物治疗对该途径的影响。方法和结果：在这里，我们证明他汀类药物治疗与高危患者人群中冠状动脉钙化升高独立相关，并且他汀类药物会破坏 Rac1 与其抑制剂 RhoGDI（Rho GDP 解离抑制剂）之间的复合物，导致原发灶中活性（GTP 结合）Rac1 增加。单核细胞/巨噬细胞。通过使用异戊二烯基前体香叶基香叶基二磷酸进行拯救，可以防止 Rac1 激活。他汀处理的巨噬细胞表现出 NF-κB（活化 B 细胞的核因子 kappa-轻链增强子）的活化增加，IL-1β mRNA 增加，以及响应炎性体刺激的 Rac1 依赖性 IL-1β 蛋白分泌增加。使用钙化性动脉粥样硬化的动物模型，在致动脉粥样硬化饮食中加入他汀类药物导致动脉粥样硬化钙化的骨髓 Rac1 依赖性增加，这与血清 IL-1β 表达增加、斑块 Rac1 活化增加以及成骨标志物、碱性磷酸酶和 RUNX2（Runt 相关转录因子 2）的斑块表达增加有关。结论 他汀类药物能够通过抑制巨噬细胞 Rac1-IL-1β 信号轴来增加动脉粥样硬化钙化。