Although susceptibility to cardiovascular disease (CVD) is different for every patient, why some patients with type 2 diabetes mellitus (T2DM) develop CVD while others are protected has not yet been clarified. Using T2DM-patient-derived human induced pluripotent stem cells (hiPSCs), we found that in patients protected from CVD, there was significantly elevated expression of an esterase, arylacetamide deacetylase (AADAC), in vascular smooth muscle cells (VSMCs). We overexpressed this esterase in human primary VSMCs and VSMCs differentiated from hiPSCs and observed that the number of lipid droplets was significantly diminished. Further metabolomic analyses revealed a marked reduction in storage lipids and an increase in membrane phospholipids, suggesting changes in the Kennedy pathway of lipid bioassembly. Cell migration and proliferation were also significantly decreased in AADAC-overexpressing VSMCs. Moreover, apolipoprotein E (Apoe)-knockout mice overexpressing VSMC-specific Aadac showed amelioration of atherosclerotic lesions. Our findings suggest that higher AADAC expression in VSMCs protects T2DM patients from CVD.

尽管每个患者对心血管疾病 (CVD) 的易感性不同，但为什么一些 2 型糖尿病 (T2DM) 患者会发展为 CVD 而另一些患者受到保护尚未阐明。使用 T2DM 患者来源的人诱导多能干细胞 (hiPSC)，我们发现在免受 CVD 保护的患者中，血管平滑肌细胞 (VSMC) 中酯酶、芳基乙酰胺脱乙酰酶 (AADAC) 的表达显着升高。我们在人类原代 VSMC 和从 hiPSC 分化的 VSMC 中过度表达了这种酯酶，并观察到脂滴的数量显着减少。进一步的代谢组学分析揭示了储存脂质的显着减少和膜磷脂的增加，表明脂质生物组装的肯尼迪途径发生了变化。在 AADAC 过表达的 VSMC 中，细胞迁移和增殖也显着降低。此外，过表达 VSMC 特异性 Aadac 的载脂蛋白 E (Apoe) 敲除小鼠显示动脉粥样硬化病变的改善。我们的研究结果表明，VSMC 中较高的 AADAC 表达可保护 T2DM 患者免受 CVD。