Effect of azelnidipine on angiotensin II-mediated growth-promoting signaling in vascular smooth muscle cells
Effect of azelnidipine on angiotensin II-mediated growth-promoting signaling in vascular smooth muscle cells
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DOI：
10.1124/mol.104.008144
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发表时间：
2005-05-01
影响因子：
3.6
通讯作者：
Horiuchi, M
中科院分区：
文献类型：
--
作者：
Li, JM;Iwai, M;Horiuchi, M
细胞外Ca ~（2+）通道阻断对血管平滑肌细胞（VSMCs）中血管紧张素Ⅱ（Ang Ⅱ）1型受体（AT 1）介导的促生长信号的影响的详细机制尚未完全了解。Ang II刺激引起促生长信号的双相激活，在5至10 min达到峰值，随后降低，在2至4 h左右达到第二个峰值。加入PD 98059（2 '-氨基-3'-甲氧基黄酮），一种促分裂原活化蛋白激酶/细胞外信号调节激酶激酶抑制剂，或AG 490 [α-氰基-（3，4-二羟基）-N-苄基肉桂酰胺]，一种Janus活化激酶2（Jak 2）抑制剂，即使在Ang II处理后4小时也抑制[H-3]胸苷掺入。钙通道阻滞剂阿折地平减弱了细胞外信号调节激酶（ERK）、酪氨酸激酶2、Jak 2激活以及信号转导和转录激活因子（STAT）1和STAT 3的磷酸化的后期峰值。有趣的是，阿折地平增加，而不是减少后ERK峰在细胞用小干扰RNA对丝裂原活化蛋白激酶磷酸酶-1。阿折地平和阿折地平加奥美沙坦剂量依赖性地抑制Ang II介导的[H-3]胸苷掺入，而奥美沙坦或阿折地平单独在这样低的剂量不影响[H-3]胸苷掺入。这些数据提供了新的见解的方式，钙通道发挥AT 1受体介导的VSMCs的促生长作用的基本行动。
The detailed mechanism of the effects of extracellular Ca2+ entry blockade on angiotensin II ( Ang II) type 1 ( AT1) receptor-mediated growth-promoting signals in vascular smooth muscle cells (VSMCs) is not fully understood. Ang II stimulation caused biphasic activation of growth-promoting signals, reaching a peak at 5 to 10 min followed by a decrease and a second peak at around 2 to 4 h. Addition of PD98059 (2'-amino-3'- methoxyflavone), a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor, or AG490 [alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide], a Janus-activated kinase 2 (Jak2) inhibitor, even 4 h after Ang II treatment inhibited [H-3] thymidine incorporation. The calcium channel blocker azelnidipine attenuated the later peaks of extracellular signal-regulated kinasenase (ERK), tyrosine kinase 2, Jak2 activation, and phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT3. Interestingly, azelnidipine increased rather than decreased the later ERK peaks in cells treated with small interfering RNA against mitogen-activated protein kinase phosphatase-1. Ang II-mediated [H-3] thymidine incorporation was inhibited dose dependently by azelnidipine and also by azelnidipine, plus olmesartan, whereas olmesartan or azelnidipine alone at such lower doses did not affect [H-3] thymidine incorporation. These data provide new insight into the manner in which calcium channels exert an essential action in the AT1 receptor-mediated growth-promoting actions in VSMCs.