De-SUMOylation enzyme of sentrin/SUMO-specific protease 2 regulates disturbed flow-induced SUMOylation of ERK5 and p53 that leads to endothelial dysfunction and atherosclerosis.
De-SUMOylation enzyme of sentrin/SUMO-specific protease 2 regulates disturbed flow-induced SUMOylation of ERK5 and p53 that leads to endothelial dysfunction and atherosclerosis.
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DOI：
10.1161/circresaha.111.300179
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发表时间：
2013-03-15
影响因子：
20.1
通讯作者：
Abe J
中科院分区：
文献类型：
--
作者：
Heo KS;Chang E;Le NT;Cushman H;Yeh ET;Fujiwara K;Abe J
血流紊乱会诱导内皮细胞 (EC) 发生促炎和凋亡反应，导致其功能失调，进而导致动脉粥样硬化。尽管在内皮细胞凋亡和炎症期间检测到的 p53 和 ERK5 的 SUMO 化之间可能存在联系，但其机制，特别是在促动脉粥样硬化血流条件下，仍然很大程度上未知。 p53 和 ERK5 的 SUMO 化是由扰动流诱导的，而不是由稳定层流诱导的。为了检查受干扰的血流诱导的 p53 和 ERK5 SUMO 化的作用，我们利用了 Sentrin/SUMO 特异性蛋白酶 2 缺陷 (Senp2+/-) 小鼠的去 SUMO 化酶，并观察到体外和体内内皮细胞凋亡和粘附分子表达显着增加。然而，这些增加在过表达 p53 和 ERK5 SUMOylation 位点突变体的 EC 中受到显着抑制。 Senp2+/- 小鼠表现出沿着内皮滚动的白细胞增加，并且在 Senp2+/-/Ldlr−/− 中观察到动脉粥样硬化病变的加速形成，但在喂食高胆固醇饮食的小鼠中观察到 Senp2+/+/Ldlr−/− 则没有。值得注意的是，Senp2+/−/Ldlr−/− 小鼠主动脉弓的病变范围比降主动脉大得多，这也表明血流紊乱诱导的蛋白质（包括 p53 和 ERK5）的 SUMO 化在动脉粥样硬化形成中发挥着至关重要的作用。这些数据显示了SENP2在血流紊乱下对内皮功能的独特作用，并表明血流紊乱对p53和ERK5的SUMO化有助于动脉粥样硬化斑块的形成。参与这种新发现的信号传导的分子将成为控制内皮细胞功能障碍并进而控制动脉粥样硬化形成的有用靶标。
Disturbed flow induces pro-inflammatory and apoptotic responses in endothelial cells (ECs), causing them to become dysfunctional and subsequently pro-atherogenic. Although a possible link between SUMOylation of p53 and ERK5 detected during endothelial apoptosis and inflammation has been suggested, the mechanistic insights, especially under the pro-atherogenic flow condition, remain largely unknown. SUMOylation of p53 and ERK5 was induced by disturbed flow but not by steady laminar flow. To examine the role of the disturbed flow-induced p53 and ERK5 SUMOylation, we utilized de-SUMOylation enzyme of sentrin/SUMO-specific protease 2 deficiency (Senp2+/−) mice and observed a significant increase in endothelial apoptosis and adhesion molecule expression both in vitro and in vivo. These increases, however, were significantly inhibited in ECs overexpressing p53 and ERK5 SUMOylation site mutants. Senp2+/− mice exhibited increased leukocyte rolling along the endothelium, and accelerated formation of atherosclerotic lesions was observed in Senp2+/−/Ldlr−/−, but not Senp2+/+/Ldlr−/−, mice fed a high cholesterol diet. Notably, the extent of lesion size in the aortic arch of Senp2+/−/Ldlr−/− mice was much larger than that in the descending aorta, also suggesting a crucial role of the disturbed flow-induced SUMOylation of proteins including p53 and ERK5 in atherosclerosis formation. These data show the unique role of SENP2 on endothelial function under disturbed flow and suggest that SUMOylation of p53 and ERK5 by disturbed flow contributes to the atherosclerotic plaque formation. Molecules involved in this newly discovered signaling will be useful targets for controlling ECs dysfunction and consequently atherosclerosis formation.