Effects of olmesartan, an AT1 receptor antagonist, on hypoxia-induced activation of ERK1/2 and pro-inflammatory signals in the mouse lung
Effects of olmesartan, an AT1 receptor antagonist, on hypoxia-induced activation of ERK1/2 and pro-inflammatory signals in the mouse lung
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DOI：
10.1007/s00210-006-0110-1
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发表时间：
2006-12-01
影响因子：
3.6
通讯作者：
Nakayama, Koichi
中科院分区：
文献类型：
--
作者：
Tanabe, Yoshiyuki;Morikawa, Yuki;Nakayama, Koichi
本研究旨在观察血管紧张素II受体1型(AT1)拮抗剂奥美沙坦对低压低氧早期小鼠右心室和肺组织细胞外信号调节蛋白(ERK)1/2激活、组织重塑和促炎信号的影响。ERK1/2在两种组织中对缺氧的反应在1-3天达到高峰，在右心室迅速下降，而在肺至少持续8天。低氧后4~9天，血管紧张素原基因在缺氧组肺中表达上调，而在缺氧性右心室和肺动脉中未见表达。奥美沙坦可抑制低氧诱导的肺组织中ERK1/2的磷酸化，但不抑制右心室中ERK1/2的磷酸化。奥美沙坦不能改善右室肥厚和肺内动脉壁增厚。然而，这种药物抑制了低氧肺中血管紧张素原和几种促炎因子的mRNA的表达，包括白细胞介素6和诱导型一氧化氮合酶。这些结果表明，奥美沙坦阻断了血管紧张素II-AT1受体系统的一个潜在的正反馈环，该环可能导致与缺氧性肺动脉高压相关的小鼠肺内促炎信号的减弱，而不会在暴露于低压低氧环境的早期阶段对代偿性心肺肥厚产生任何明显的影响。
The present study aimed to investigate the effects of olmesartan, an antagonist for angiotensin II receptor type 1(AT1), on the activation of extracellular signal-regulated kinases (ERK)1/2, tissue remodeling, and pro-inflammatory signals in the right ventricle and lung of mice during the early phase of hypobaric hypoxia. Phosphorylation of ERK1/2 in both tissue types in response to hypoxia peaked at 1-3 days, and declined rapidly in the right ventricle, whereas in the lung it was sustained for at least 8 days. Upregulation of angiotensinogen mRNA was observed in the hypoxic lung at 4-9 days, but not in the hypoxic right ventricle and pulmonary artery. Olmesartan inhibited the hypoxia-induced phosphorylation of ERK1/2 in the lung, but not in the right ventricle. Neither right ventricular hypertrophy nor the thickening of the intrapulmonary arterial wall was ameliorated by olmesartan. However, this drug inhibited the expression of the mRNA for angiotensinogen and several pro-inflammatory factors, including interleukin-6 and inducible nitric oxide synthase in the hypoxic lung. These results suggest that olmesartan blocks a potential positive feedback loop of the angiotensin II-AT1 receptor system, which may lead to attenuate pro-inflammatory signals in the mouse lung, that are associated with hypoxic pulmonary hypertension, without inducing any appreciable effects on the compensatory cardiopulmonary hypertrophy at an early phase of exposure to a hypobaric hypoxic environment.