Inhibition of Caspase-1 Activation in Endothelial Cells Improves Angiogenesis A NOVEL THERAPEUTIC POTENTIAL FOR ISCHEMIA
Inhibition of Caspase-1 Activation in Endothelial Cells Improves Angiogenesis A NOVEL THERAPEUTIC POTENTIAL FOR ISCHEMIA
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DOI：
10.1074/jbc.m115.641191
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发表时间：
2015-07-10
影响因子：
4.8
通讯作者：
Yang, Xiao-Feng
中科院分区：
文献类型：
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作者：
Lopez-Pastrana, Jahaira;Ferrer, Lucas M.;Yang, Xiao-Feng
血管生成不足可能导致心肌缺血、外周动脉疾病、缺血性中风等的预后恶化。血脂异常和炎症环境会减弱内皮细胞（EC）增殖和血管生成，使缺血的预后恶化。在这些血脂异常和炎症环境下，EC-caspase-1 被激活并诱导炎症细胞死亡，即细胞焦亡。然而，将 caspase-1 激活与血管生成损伤以及缺血预后相关的潜在机制仍不清楚。通过使用流式细胞术分析、酶和受体抑制剂以及 caspase-1 敲除 (KO) 小鼠的后肢缺血模型，我们检验了我们的新假设，即在血脂异常和炎症环境下抑制 EC 中的 caspase-1 可减轻 EC 焦亡，改善血管内皮生长因子受体 2 (VEGFR-2) 介导的 EC 存活、血管生成和缺血预后。我们得出以下结论。促动脉粥样硬化脂质在较大尺寸的人主动脉内皮细胞 (HAEC) 中比在较小尺寸的 HAEC 中诱导更高的 caspase-1 活化。促动脉粥样硬化脂质在较小尺寸的 HAEC 中比在较大尺寸的细胞中更显着地增加细胞焦亡。 VEGFR-2 抑制会增加溶血磷脂酰胆碱治疗诱导的 HAEC 中 caspase-1 的激活。 Caspase-1 激活抑制 VEGFR-2 表达。 Caspase-1 抑制可改善经溶血磷脂酰胆碱处理的 HAEC 的管形成。最后，caspase-1 消耗可改善小鼠后肢缺血组织中的血管生成和血流。我们的结果首次证明，抑制内皮细胞中促动脉粥样硬化的 caspase-1 激活可改善血管生成和缺血的预后。
Deficient angiogenesis may contribute to worsen the prognosis of myocardial ischemia, peripheral arterial disease, ischemic stroke, etc. Dyslipidemic and inflammatory environments attenuate endothelial cell (EC) proliferation and angiogenesis, worsening the prognosis of ischemia. Under these dyslipidemic and inflammatory environments, EC-caspase-1 becomes activated and induces inflammatory cell death that is defined as pyroptosis. However, the underlying mechanism that correlates caspase-1 activation with angiogenic impairment and the prognosis of ischemia remains poorly defined. By using flow cytometric analysis, enzyme and receptor inhibitors, and hind limb ischemia model in caspase-1 knock-out (KO) mice, we examined our novel hypothesis, i.e. inhibition of caspase-1 in ECs under dyslipidemic and inflammatory environments attenuates EC pyroptosis, improves EC survival mediated by vascular endothelial growth factor receptor 2 (VEGFR-2), angiogenesis, and the prognosis of ischemia. We have made the following findings. Proatherogenic lipids induce higher caspase-1 activation in larger sizes of human aortic endothelial cells (HAECs) than in smaller sizes of HAECs. Proatherogenic lipids increase pyroptosis significantly more in smaller sizes of HAECs than in larger sizes of the cells. VEGFR-2 inhibition increases caspase-1 activation in HAECs induced by lysophosphatidylcholine treatment. Caspase-1 activation inhibits VEGFR-2 expression. Caspase-1 inhibition improves the tube formation of lysophosphatidylcholine-treated HAECs. Finally, caspase-1 depletion improves angiogenesis and blood flow in mouse hind limb ischemic tissues. Our results have demonstrated for the first time that inhibition of proatherogenic caspase-1 activation in ECs improves angiogenesis and the prognosis of ischemia.