Molecular and cellular mechanism of angiotensin II-mediated apoptosis
Molecular and cellular mechanism of angiotensin II-mediated apoptosis
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DOI：
10.3109/07435809809032610
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发表时间：
1998-01-01
影响因子：
2.1
通讯作者：
Dzau, VJ
中科院分区：
文献类型：
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作者：
Horiuchi, M;Akishita, M;Dzau, VJ
众所周知，血管紧张素II通过血管紧张素II 1型（ATI）受体发挥生长促进作用。我们已经克隆了第二种类型的血管紧张素II受体（AT 2受体），并证明这种受体作为一种拮抗受体对ATI受体。此外，我们已经证明，AT 2受体通过拮抗ATI受体和生长因子在几种细胞系包括血管平滑肌细胞、心肌细胞、神经元细胞（PC 12 W）和成纤维细胞（R3 T3）中的作用而发挥生长抑制和促凋亡作用。我们观察到An受体激活酪氨酸磷酸酶，如丝裂原活化蛋白（MAP）激酶-磷酸酶-1（MKP-1），并使MAP激酶（细胞外信号调节激酶（ERK 1和ERK 2））失活，导致Bcl-2去磷酸化和Bar上调。ERK的这种失活通过Gi蛋白偶联通过其独特的细胞内第三环介导。此外，我们已经证明，干扰素调节因子（IRF）-1也上调凋亡细胞中的AT 2受体，这表明细胞因子可能在血管紧张素调节的细胞凋亡中发挥重要作用。
It is well known that angiotensin II exerts growth promoting effects via the angiotensin II type 1 (ATI) receptor. We have cloned a a second type of angiotensin II receptor (AT2 receptor) and demonstrated that this receptor acts as an antagonistic receptor against the ATI receptor. Moreover, we have demonstrated that the AT2 receptor exerts growth inhibitory and proapoptotic effects by antagonizing the effects of the ATI receptor and growth factors in several cell lines including vascular smooth muscle cells, cardiomyocytes, neuronal cell (PC12W) and fibroblasts (R3T3). We observed that the An receptor activates tyrosine phosphatase(s) such as mitogen-activated protein (MAP) kinase-phosphatase-1 (MKP-1) and inactivates MAP kinase (extracellular signal-regulated kinase (ERK1 and ERK2)), resulting in Bcl-2 dephosphorylation and up-regulation of Bar. This inactivation of ERK is mediated via Gi protein coupling through its unique intracellular third loop. Moreover, we have demonstrated that interferon regulatory factor(IRF)-1 also up-regulates the AT2 receptor in apoptotic cells, suggesting that the cytokines may play an important role in angiotensin-regulated apoptosis.