Activation of MAPKs by angiotensin II in vascular smooth muscle cells - Metalloprotease-dependent EGF receptor activation is required for activation of ERK and p38 MAPK but not for JNK
Activation of MAPKs by angiotensin II in vascular smooth muscle cells - Metalloprotease-dependent EGF receptor activation is required for activation of ERK and p38 MAPK but not for JNK
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DOI：
10.1074/jbc.m008570200
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发表时间：
2001-03-16
影响因子：
4.8
通讯作者：
Inagami, T
中科院分区：
文献类型：
--
作者：
Eguchi, S;Dempsey, PJ;Inagami, T
在培养的血管平滑肌细胞（VSMC）中，血管营养因子血管紧张素II（AngII）通过G（q）偶联AT（1）受体激活三种主要MAPK。细胞外信号调节激酶（ERK）激活血管紧张素Ⅱ需要钙依赖性的“反式激活”的EGF受体，可能涉及一种金属蛋白酶，以刺激加工的EGF受体配体从其前体。EGF受体反式激活是否也有助于通过AngII激活MAPK的其他成员，如p38 MAPK和c-Jun N-末端激酶（JNK）仍不清楚。在本研究中，我们检测了合成的金属蛋白酶抑制剂BB 2116和EGF受体激酶抑制剂AG 1478对血管紧张素Ⅱ诱导的VSMC MAPK活化的影响，BB 2116显著抑制由血管紧张素Ⅱ或Ca ~（2+）离子载体A23187诱导的ERK活化，而不影响EGF或PDGF的活化，BB 2116和HB-EGF中和抗体可抑制AngII对EGF受体的反式激活作用，提示HB-EGF在金属蛋白酶依赖的EGF受体反式激活中起关键作用。除ERK激活外，AT（1）受体拮抗剂RNH 6270还可抑制AngII对p38 MAPK和JNK的激活。A23187和EGF能显著激活p38 MAPK，而A23187却不能显著激活JNK，提示EGF受体的反式激活可能参与了p38 MAPK的激活。BB 2116和AG 1478均能特异性抑制AngII激活p38 MAPK而非JNK，这一发现支持了这一假说。从这些数据中，我们得出结论，ERK和p38 MAPK激活血管生成素II需要的金属蛋白酶依赖性的EGF受体的反式激活，而JNK的激活调节没有参与EGF受体的反式激活。
In cultured vascular smooth muscle cells (VSMC), the vasculotrophic factor, angiotensin II (AngII) activates three major MAPKs via the G(q)-coupled AT(1) receptor. Extracellular signal-regulated kinase (ERK) activation by AngII requires Ca2+-dependent "transactivation" of the EGF receptor that may involve a metalloprotease to stimulate processing of an EGF receptor ligand from its precursor. Whether EGF receptor transactivation also contributes to activation of other members of MAPKs such as p38MAPK and c-Jun N-terminal kinase (JNK) by AngII remains unclear. In the present study, we have examined the effects of a synthetic metalloprotease inhibitor BB2116, and the EGF receptor kinase inhibitor AG1478 on AngII-induced activation of MAPKs in cultured VSMC, BB2116 markedly inhibited ERK activation induced by AngII or the Ca2+ ionophore A23187 without affecting the activation by EGF or PDGF, BB2116 as well as HB-EGF neutralizing antibody inhibited the EGF receptor transactivation by AngII, suggesting a critical role of HB-EGF in the metalloprotease-dependent EGF receptor transactivation. In addition to the ERK activation, activation of p38MAPK and JNK by AngII was inhibited by an AT(1) receptor antagonist, RNH6270. A23187 and EGF markedly activate p38MAPK, whereas A23187 but not EGF markedly activates JNK, indicating the possible contribution of the EGF receptor transactivation to the p38MAPK activation, The findings that both BB2116 and AG1478 specifically inhibited activation of p38MAPK but not JNK by AngII support this hypothesis. From these data, we conclude that ERK and p38MAPK activation by AngII requires the metalloprotease-dependent EGF receptor transactivation, whereas the JNK activation is regulated without involvement of EGF receptor transactivation.