Phosphatidylinositol 3-kinase/Akt regulates angiotensin II-induced inhibition of apoptosis in microvascular endothelial cells by governing survivin expression and suppression of caspase-3 activity
Phosphatidylinositol 3-kinase/Akt regulates angiotensin II-induced inhibition of apoptosis in microvascular endothelial cells by governing survivin expression and suppression of caspase-3 activity
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DOI：
10.1161/01.res.0000121103.03275.ec
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发表时间：
2004-04-02
影响因子：
20.1
通讯作者：
Honda, Y
中科院分区：
文献类型：
--
作者：
Ohashi, H;Takagi, H;Honda, Y
血管紧张素II（Ang II）在血管稳态、新生内膜形成和梗死后重塑中起重要作用。虽然血管紧张素II已被证明可以调节心肌细胞和血管平滑肌细胞的凋亡，但其在血管内皮细胞（ECs）中的作用仍不清楚。为了解决这个问题，我们首先进行TUNEL和caspase-3活性测定与猪微血管内皮细胞的血清剥夺的挑战。Ang Ⅱ显著降低凋亡细胞比例和caspase-3活性。血管紧张素Ⅱ 1型受体（AT（1））负责这些作用。在AT 1下游的信号分子中，我们发现PI 3-激酶/Akt途径在Ang II的抗凋亡作用中发挥主导作用。有趣的是，细胞存活的中心分子存活素的表达在Ang II刺激后增加。显性负性Akt的过度表达可同时抑制Ang II诱导的抗凋亡和Survivin蛋白的表达。在高氧诱导的视网膜血管退化的小鼠模型中，AT（1a）基因敲除小鼠的视网膜无血管面积显著增加。我们的数据表明，血管紧张素II在血管内皮细胞中起着关键的抗凋亡作用，其机制涉及PI 3-激酶/Akt激活，随后上调生存素，抑制caspase-3活性。
Angiotensin II (Ang II) plays essential roles in vascular homeostasis, neointimal formation, and postinfarct remodeling. Although Ang II has been shown to regulate apoptosis in cardiomyocytes and vascular smooth muscle cells, its role in vascular endothelial cells (ECs) remains elusive. To address this issue, we first performed TUNEL and caspase-3 activity assays with porcine microvascular ECs challenged by serum deprivation. Ang II significantly reduced the ratio of apoptotic cells and caspase-3 activity. The Ang II type 1 receptor (AT(1)) was responsible for these effects. Among the signaling molecules downstream of AT1, we revealed that PI3-kinase/Akt pathway plays a predominant role in the antiapoptotic effect of Ang II. Interestingly, the expression of survivin, a central molecule of cell survival, increased after Ang II stimulation. Overexpression of a dominant-negative form of Akt abolished both Ang II - induced antiapoptosis and survivin protein expression. In a murine model of hyperoxygen-induced retinal vascular regression, AT(1a) knockout mice showed a significant increase in retinal avascular areas. Our data indicate that Ang II plays a critical antiapoptotic role in vascular ECs by a mechanism involving PI3-kinase/Akt activation, subsequent upregulation of survivin, and suppression of caspase-3 activity.