Li Qian, Fu Jialin, Park Kyoungmin, Shah Hetal, Li Qin, Wu I Hsien, King George L
Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
Department of Medicine, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
Cardiovasc Res. 2024 Dec 14;120(16):2017-2030. doi: 10.1093/cvr/cvae193.
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.
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.
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.
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风险升高有关，这些斑块的特征是血管平滑肌细胞（VSMC）和细胞外基质（ECM）减少以及炎症增加。因此，胰岛素抵抗可能会降低斑块稳定性，因为在VSMC中删除胰岛素受体（IR）会降低其增殖并增强细胞凋亡。
使用VSMC中ApoE和IR基因双敲除的小鼠（SMIRKO/ApoE-/-、Myh11-CreERT2EYFP+/ApoE-/-和Myh11-CreERT2EYFP+IRKO/ApoE-/-小鼠）研究胰岛素对VSMC改变斑块组成的直接作用，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VSMC和胶原蛋白含量较少，但VSMC凋亡水平和坏死区域增加。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-/-小鼠主动脉中的这种细胞增加。缺乏IR的分离VSMC比具有IR的细胞表达更高的炎症细胞因子。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IR/Akt途径的激活介导的，在SMIRKO或高脂饮食小鼠的VSMC中这种作用减弱。对调节VSMC中炎症细胞因子的IR靶点分析表明，随着IR缺失，血小板反应蛋白1（Thbs1）和Mmp2持续增加。胰岛素通过p-Akt/p-FoxO1途径抑制ApoE-/-小鼠VSMC中Thbs1的表达，但不抑制Mmp2的表达，而在SMIRKO/ApoE-/-小鼠的细胞中这种抑制作用受损。Thbs1进一步诱导VSMC中Icam1和Mmp2的表达。
胰岛素通过IR在VSMC中具有显著作用，通过激活Akt和FoxO1途径减少炎症、细胞凋亡和ECM周转。胰岛素作用以及与胰岛素抵抗和糖尿病相关途径的抑制可能有助于不稳定动脉粥样硬化斑块的形成。
