p38 mitogen-activated protein kinase is a critical component of the redox-sensitive signaling pathways activated by angiotensin II - Role in vascular smooth muscle cell hypertrophy
p38 mitogen-activated protein kinase is a critical component of the redox-sensitive signaling pathways activated by angiotensin II - Role in vascular smooth muscle cell hypertrophy
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DOI：
10.1074/jbc.273.24.15022
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发表时间：
1998-06-12
影响因子：
4.8
通讯作者：
Griendling, KK
中科院分区：
文献类型：
--
作者：
Ushio-Fukai, M;Alexander, RW;Griendling, KK
血管紧张素II诱导培养的血管平滑肌细胞氧化应激依赖性肥大。为了研究H2 O2的生长相关分子靶点，我们研究了促分裂原活化蛋白激酶（MAPK）家族激动剂刺激活化的氧化还原敏感性。我们发现血管紧张素II可使细胞内H2 O2迅速增加，并使p42/44 MAPK和p38 MAPK磷酸化迅速增强（分别增强16倍和15倍）。然而，外源性H2 O2仅激活p38 MAPK（14倍），和二苯碘鎓，一种NADH/NADPH氧化酶抑制剂，减弱血管紧张素II刺激的p38 MAPK磷酸化，但不p42/44 MAPK。此外，在稳定转染人过氧化氢酶的细胞中，血管紧张素II诱导的细胞内H2 O2的产生几乎完全被阻断，导致p38 MAPK磷酸化的抑制，而不是p42/44 MAPK，以及随后的血管紧张素II诱导的肥大的部分减少。SB 203580对p38 MAPK通路的特异性抑制（4-（4-氟苯基）-2-（4-甲基亚磺酰基苯基）-5-（4-吡啶基）1H-咪唑）或PD 98059的p42/44 MAPK途径（2-（2 '-氨基-3'-甲氧基苯基）氧萘-4-酮）也部分但显著地减弱血管紧张素II诱导的肥大;然而，同时阻断这两条途径具有相加的抑制作用，表明对血管紧张素II的肥大反应需要两条MAPK途径的平行、独立激活。这些结果提供了第一个证据表明，p38 MAPK是血管平滑肌细胞中血管紧张素II激活的氧化应激（H2 O2）敏感信号通路的关键组成部分，并表明它在血管肥大中起着至关重要的作用。
Angiotensin II induces an oxidant stress-dependent hypertrophy in cultured vascular smooth muscle cells. To investigate the growth-related molecular targets of H2O2, we examined the redox sensitivity of agonist-stimulated activation of the mitogen-activated protein kinase (MAPK) family. We show here that angiotensin II elicits a rapid increase in intracellular H2O2 and a rapid and robust phosphorylation of both p42/44MAPK (16-fold) and p38MAPK (15-fold). However, exogenous H2O2 activates only p38MAPK (14-fold), and diphenylene iodonium, an NADH/NADPH oxidase inhibitor, attenuates angiotensin II-stimulated phosphorylation of p38MAPK, but not p42/44MAPK. Furthermore, in cells stably transfected with human catalase, angiotensin II-induced intracellular H2O2 generation is almost completely blocked, resulting in inhibition of phosphorylation of p38MAPK,, but not p42/44MAPK, and a subsequent partial decrease in angiotensin II-induced hypertrophy. Specific inhibition of either the p38MAPK pathway with SB203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole) or the p42/44MAPK pathway with PD98059 (2-(2'-amino-3'-methoxyphenyl)oxanaphthalen-4-one) also partially, but significantly, attenuates angiotensin II-induced hypertrophy; however, simultaneous blockade of both pathways has an additive inhibitory effect, indicating that the hypertrophic response to angiotensin II requires parallel, independent activation of both MAPK pathways. These results provide the first evidence that p38MAPK is a critical component of the oxidant stress (H2O2)-sensitive signaling pathways activated by angiotensin II in vascular smooth muscle cells and indicate that it plays a crucial role in vascular hypertrophy.