Prolonged Hypoxia Increases ROS Signaling and RhoA Activation in Pulmonary Artery Smooth Muscle and Endothelial Cells
Prolonged Hypoxia Increases ROS Signaling and RhoA Activation in Pulmonary Artery Smooth Muscle and Endothelial Cells
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DOI：
10.1089/ars.2009.2861
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发表时间：
2010-03-01
影响因子：
6.6
通讯作者：
Schumacker, Paul T.
中科院分区：
文献类型：
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作者：
Chi, Annie Y.;Waypa, Gregory B.;Schumacker, Paul T.
缺氧性肺血管收缩（HPV）反应的I期开始于向缺氧的转变，并涉及胞浆钙（[Ca 2 +]（i））的增加。II期在长时间缺氧期间发展，涉及收缩增加而[Ca 2 +]（i）没有进一步增加，表明Ca 2+敏感性增加。长时间缺氧激活RhoA和RhoA激酶，这可能增加Ca 2+敏感性，但机制尚不清楚。我们以前发现活性氧（ROS）触发I相。因此，我们问是否在长时间缺氧过程中ROS的产生激活RhoA在PA平滑肌细胞（PASMCs）和内皮细胞（PAECs）在第二阶段。通过使用细胞溶质氧化还原传感器RoGFP，我们检测到PASMCs（29.8 +/- 1.3%至39.8 +/- 1.4%）和PAEC（25.9 +/- 2.1%至43.7.9 +/- 3.5%）中长时间缺氧时氧化剂信号传导增加，这在恢复正常氧时被逆转，并且在两种细胞类型中被EUK-134减弱。在长时间缺氧（6.4 +/- 1.2倍和5.8 +/- 1.6倍）和外源性H2 O2（分别为4.1和2.3倍）期间，PASMCs和PAECs中RhoA活性增加。然而，废除ROS信号在PASMCs或PAECs与EUK-134或缺氧未能减弱增加的RhoA活性。因此，ROS信号在PASMC和PAEC中的长时间缺氧期间持续，并且这对于RhoA激活是足够的但不是必需的。抗氧化剂。氧化还原信号。12，603-610.
Phase I of the hypoxic pulmonary vasoconstriction (HPV) response begins upon transition to hypoxia and involves an increase in cytosolic calcium ([Ca2+](i)). Phase II develops during prolonged hypoxia and involves increases in constriction without further increases in [Ca2+](i), suggesting an increase in Ca2+ sensitivity. Prolonged hypoxia activates RhoA and RhoA kinase, which may increase Ca2+ sensitivity, but the mechanism is unknown. We previously found that reactive oxygen species (ROS) trigger Phase I. We therefore asked whether ROS generation during prolonged hypoxia activates RhoA in PA smooth muscle cells (PASMCs) and endothelial cells (PAECs) during Phase II. By using a cytosolic redox sensor, RoGFP, we detected increased oxidant signaling in prolonged hypoxia in PASMCs (29.8 +/- 1.3% to 39.8 +/- 1.4%) and PAECs (25.9 +/- 2.1% to 43.7.9 +/- 3.5%), which was reversed on the return to normoxia and was attenuated with EUK-134 in both cell types. RhoA activity increased in PASMCs and PAECs during prolonged hypoxia (6.4 +/- 1.2-fold and 5.8 +/- 1.6-fold) and with exogenous H2O2 (4.1- and 2.3-fold, respectively). However, abrogation of the ROS signal in PASMCs or PAECs with EUK-134 or anoxia failed to attenuate the increased RhoA activity. Thus, the ROS signal is sustained during prolonged hypoxia in PASMCs and PAECs, and this is sufficient but not required for RhoA activation. Antioxid. Redox Signal. 12, 603-610.