Aims Increased prevalence of acute myocardial infarction related to diabetes and insulin resistance is associated with an elevated risk of unstable atherosclerotic plaques, which are characterized by reduced vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM) and increased inflammation. Thus, insulin resistance may reduce plaque stability, as deleting insulin receptors (IRs) in VSMCs decreases their proliferation and enhances apoptosis. Methods and results Direct effects of insulin on VSMCs to alter plaque composition were studied using mice with double knockout of ApoE and IR genes in VSMCs with SMIRKO/ApoE−/−, Myh11-CreERT2EYFP+/ApoE−/−, and Myh11-CreERT2EYFP+IRKO/ApoE−/− mice, which were also used for lineage tracing studies. Compared with ApoE−/− mice, SMIRKO/ApoE−/− mice exhibited more atherosclerotic plaques, which contained less VSMCs and collagen but increased levels of VSMC apoptosis and necrotic areas. Lineage tracing studies showed that Icam1+ Vcam1+ VSMC was inflammatory, which increased in the aortas of Myh11-CreERT2EYFP+IRKO/ApoE−/− mice compared with control mice. Isolated VSMCs lacking IRs expressed higher inflammatory cytokines than cells with IRs. Cell-based studies indicated that insulin’s anti-apoptotic and pro-proliferative effects in VSMCs were mediated via activation of the IR/Akt pathway, which were decreased in VSMCs from SMIRKO or high-fat diet mice. An analysis of the IR targets that regulated inflammatory cytokines in VSMCs showed that thrombospondin 1 (Thbs1) and Mmp2 were consistently increased with a loss of IRs. Insulin inhibited Thbs1 expression, but not Mmp2 expression, through p-Akt/p-FoxO1 pathways in VSMCs from ApoE−/− mice, and was impaired in cells from SMIRKO/ApoE−/− mice. Thbs1 further induced Icam1 and Mmp2 expressions in VSMCs. Conclusion Insulin via IRs has significant actions in VSMCs to decrease inflammation, apoptosis, and ECM turnover via the activation of Akt and FoxO1 pathways. The inhibition of insulin actions and related pathways related to insulin resistance and diabetes may contribute to the formation of unstable atherosclerotic plaques.

中文翻译：

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血管平滑肌细胞中的胰岛素受体调节动脉粥样硬化的斑块稳定性


目的 与糖尿病和胰岛素抵抗相关的急性心肌梗死患病率增加与不稳定动脉粥样硬化斑块的风险增加有关，其特征是血管平滑肌细胞 （VSMC） 和细胞外基质 （ECM） 减少和炎症增加。因此，胰岛素抵抗可能会降低斑块稳定性，因为删除 VSMC 中的胰岛素受体 （IR） 会减少其增殖并增强细胞凋亡。方法和结果 使用 SMIRKO/ApoE-/-、Myh11-CreERT2EYFP+/ApoE-/-和 Myh11-CreERT2EYFP+IRKO/ApoE-/-小鼠中 ApoE 和 IR 基因双重敲除的小鼠研究胰岛素对 VSMC 改变斑块组成的直接影响，这些小鼠也用于谱系追踪研究。与 ApoE - / - 小鼠相比，SMIRKO/ApoE - /- 小鼠表现出更多的动脉粥样硬化斑块，其中含有较少的 VSMC 和胶原蛋白，但 VSMC 细胞凋亡和坏死区域的水平增加。谱系追踪研究表明，Icam1 + Vcam1 + VSMC 具有炎症性，与对照小鼠相比，Myh11-CreERT2EYFP+IRKO/ApoE-/-小鼠的主动脉中炎症性增加。缺乏 IR 的分离 VSMC 比具有 IR 的细胞表达更高的炎性细胞因子。基于细胞的研究表明，胰岛素在 VSMC 中的抗凋亡和促增殖作用是通过激活 IR/Akt 通路介导的，这在 SMIRKO 或高脂饮食小鼠的 VSMC 中降低。对调节 VSMC 中炎性细胞因子的 IR 靶标的分析表明，血小板反应蛋白 1 （Thbs1） 和 Mmp2 随着 IR 的丢失而持续增加。胰岛素通过 ApoE-/-小鼠 VSMC 中的 p-Akt/p-FoxO1 通路抑制 Thbs1 表达，但不抑制 Mmp2 表达，并且在 SMIRKO/ApoE-/-小鼠细胞中受损。 Thbs1 进一步诱导 VSMCs 中 Icam1 和 Mmp2 的表达。结论 IRs 胰岛素在 VSMCs 中具有显着作用，通过激活 Akt 和 FoxO1 通路减少炎症、细胞凋亡和 ECM 周转。胰岛素作用的抑制以及与胰岛素抵抗和糖尿病相关的相关途径可能导致不稳定动脉粥样硬化斑块的形成。