Patient hiPSCs Identify Vascular Smooth Muscle Arylacetamide Deacetylase as Protective against Atherosclerosis.
Patient hiPSCs Identify Vascular Smooth Muscle Arylacetamide Deacetylase as Protective against Atherosclerosis.
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DOI：
10.1016/j.stem.2020.04.018
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发表时间：
2020-07-02
期刊：
影响因子：
23.9
通讯作者：
Cowan CA
中科院分区：
文献类型：
--
作者：
Toyohara T;Roudnicky F;Florido MHC;Nakano T;Yu H;Katsuki S;Lee M;Meissner T;Friesen M;Davidow LS;Ptaszek L;Abe T;Rubin LL;Pereira AC;Aikawa M;Cowan CA
虽然每个患者对心血管疾病（CVD）的易感性不同，但为什么一些II型糖尿病（T2DM）患者会发生CVD，而另一些患者则受到保护尚未阐明。使用T2DM患者来源的hiPSC，我们发现在免于CVD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和从hiPSC分化的VSMC中过表达这种酯酶，并观察到脂滴的数量显著减少。进一步的代谢组学分析显示，储存脂质显着减少，膜磷脂增加，这表明肯尼迪途径的脂质生物组装的变化。细胞迁移和增殖也显着降低AADAC过表达的VSMCs。此外，载脂蛋白E（Apoe）敲除小鼠过表达VSMC特异性Aadac显示动脉粥样硬化病变的改善。我们的研究结果表明，VSMCs中较高的AADAC表达可保护T2DM患者免于CVD。
Although susceptibility to cardiovascular disease (CVD) is different for every patient, why some patients with type II diabetes mellitus (T2DM) develop CVD while others are protected has not yet been clarified. Using T2DM patient-derived 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.
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影响因子：
11.1
作者：
Krahmer, Natalie;Farese, Robert V., Jr.;Walther, Tobias C.
通讯作者：
Walther, Tobias C.
2型糖尿病和心血管疾病：遗传和表观遗传联系。
影响因子：
5.2
作者：
De Rosa S;Arcidiacono B;Chiefari E;Brunetti A;Indolfi C;Foti DP
通讯作者：
Foti DP
影响因子：
4.6
作者：
Ameku T;Taura D;Sone M;Numata T;Nakamura M;Shiota F;Toyoda T;Matsui S;Araoka T;Yasuno T;Mae S;Kobayashi H;Kondo N;Kitaoka F;Amano N;Arai S;Ichisaka T;Matsuura N;Inoue S;Yamamoto T;Takahashi K;Asaka I;Yamada Y;Ubara Y;Muso E;Fukatsu A;Watanabe A;Sato Y;Nakahata T;Mori Y;Koizumi A;Nakao K;Yamanaka S;Osafune K
通讯作者：
Osafune K
影响因子：
37.8
作者：
Goldberg IJ;Reue K;Abumrad NA;Bickel PE;Cohen S;Fisher EA;Galis ZS;Granneman JG;Lewandowski ED;Murphy R;Olive M;Schaffer JE;Schwartz-Longacre L;Shulman GI;Walther TC;Chen J
通讯作者：
Chen J
DOI：
10.1161/atvbaha.114.303326
发表时间：
2014-06
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Quillard T;Araújo HA;Franck G;Tesmenitsky Y;Libby P
通讯作者：
Libby P