Department of Medicine, Division of Cardiology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA 02215, USA; Division of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Sendai, Miyagi 980-8574, Japan.
Roche pRED (Pharmaceutical Research and Early Development), Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd., Basel 4070, Switzerland.
Cell Stem Cell. 2020 Jul 2;27(1):147-157.e7. doi: 10.1016/j.stem.2020.04.018. Epub 2020 May 14.
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，而另一些患者则受到保护，目前尚未阐明。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 影响的患者中，血管平滑肌细胞 (VSMC) 中酯酶芳基乙酰胺脱乙酰酶 (AADAC) 的表达显著升高。我们在人原代 VSMC 和 hiPSC 分化的 VSMC 中过表达这种酯酶，观察到脂滴数量明显减少。进一步的代谢组学分析显示储存脂质明显减少，膜磷脂增加，提示脂质生物组装的 Kennedy 途径发生变化。AADAC 过表达的 VSMC 中细胞迁移和增殖也明显减少。此外，过表达血管平滑肌细胞特异性 Aadac 的载脂蛋白 E (Apoe) 敲除小鼠的动脉粥样硬化病变得到改善。我们的研究结果表明，VSMC 中更高的 AADAC 表达可保护 T2DM 患者免受 CVD 的影响。
