Hypoxic neonatal pulmonary arterial myocytes are sensitized to ROS-generated 8-isoprostane
Hypoxic neonatal pulmonary arterial myocytes are sensitized to ROS-generated 8-isoprostane
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DOI：
10.1016/j.freeradbiomed.2010.01.009
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发表时间：
2010-04-01
影响因子：
7.4
通讯作者：
Dakshinamurti, S.
中科院分区：
文献类型：
--
作者：
Gong, Y.;Yi, M.;Dakshinamurti, S.
8-异前列腺素是一种ros衍生的类前列腺素，通过血栓素受体（TP）起作用，与新生儿肺动脉高压有关。本研究旨在探讨缺氧对血管平滑肌ROS生成、8-异前列腺素活性和TP结合的影响。将首代新生猪肺动脉肌细胞暴露于10% O-2（低氧肌细胞；HM）或21% O-2（常氧肌细胞）中72小时。缺氧增加了体外ROS、超氧化物和8-异前列腺素的生成。通过抑制线粒体抑制ROS的产生。复杂的三世。HM组SOD1和so3活性升高，SOD2活性降低45%。8-异前列烷的生成由过氧化氢和一氧化氮的加入驱动；与渗透性PEG-SOD孵育，但不与peg -过氧化氢酶或硬性SOD孵育，减少缺氧诱导的8-异前列腺素生成。8-异前列腺素对TP的亲和力在HM中显著增加。心肌细胞8-异前列腺素激发仅在HM中引起TP内化和钙释放；这对TP阻断敏感，并通过腺苷酸环化酶的激活而正常化。我们提出，缺氧通过抑制线粒体SOD2活性诱导肺动脉肌细胞超氧化物积累，促进过氧亚硝酸盐诱导的8-异前列腺素的生成。8-异前列腺素与致敏的TP受体结合，引起受体内化，并在缺氧肌细胞中发出钙释放信号。8-异前列腺素可能是新生儿缺氧时重要的肺血管收缩剂。(C) 2010爱思唯尔公司版权所有。
8-Isoprostane, a ROS-derived prostanoid that acts via the thromboxane receptor (TP), is implicated in neonatal pulmonary hypertension. The purpose of this study was to examine the effect of hypoxia on vascular smooth muscle ROS generation, 8-isoprostane activity, and TP binding. First-passage neonatal porcine pulmonary artery myocytes were exposed to 10% O-2 (hypoxic myocytes; HM) or 21% O-2 (normoxic myocytes) for 72 h. Hypoxia increased in vitro generation of ROS, superoxide, and 8-isoprostane. ROS generation was ablated by inhibition of mitochondria! complex III. SOD1 and 3 activities were increased, but SOD2 activity decreased by 45% in HM. 8-Isoprostane generation was driven by the addition of peroxide and nitric oxide; incubation with permeative PEG-SOD, but not PEG-catalase or impermeative SOD, attenuated hypoxia-induced 8-isoprostane generation. 8-Isoprostane affinity for TP was markedly increased in HM. Myocyte 8-isoprostane challenge caused TP internalization and calcium release only in HM; this was sensitive to TP blockade and was normalized by activation of adenylyl cyclase. We propose that hypoxia induces superoxide accumulation in pulmonary artery myocytes through inhibition of mitochondrial SOD2 activity, promoting peroxynitrite-induced generation of 8-isoprostane. 8-Isoprostane binds to sensitized TP receptors, causing receptor internalization and signaling to calcium release in hypoxic myocytes. 8-Isoprostane may be an important pulmonary vasoconstrictor during neonatal hypoxia. (C) 2010 Elsevier Inc. All rights reserved.