Pulmonary vascular and cardiac effects of peroxynitrite decomposition in newborn rats
Pulmonary vascular and cardiac effects of peroxynitrite decomposition in newborn rats
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DOI：
10.1016/j.freeradbiomed.2010.07.021
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发表时间：
2010-11-01
影响因子：
7.4
通讯作者：
Jankov, Robert P.
中科院分区：
文献类型：
--
作者：
Belik, Jaques;Stevens, Danielle;Jankov, Robert P.
有证据表明氧化应激在肺动脉高压的发病机制中发挥着重要作用，其中过氧亚硝酸根阴离子（ONOO(-)）可能发挥着重要作用。假设去除ONOO（-）会减轻慢性新生儿肺动脉高压，我们研究了ONOO（-）分解催化剂（FeTPPS）对体外肺动脉、原代培养的肺动脉平滑肌细胞（PASMC）和心肌细胞存活和生长的影响，以及对出生后暴露于缺氧（13％O（2））7天的幼鼠中枢血流动力学的影响。每日 FeTPPS（30 mg/kg ip）可降低缺氧动物的肺硝基酪氨酸含量，减弱血管重塑，并使肺血管阻力正常化。 FeTPPS 在体外减弱新生儿 PASMC 的增殖并增加其凋亡。用 FeTPPS 治疗的离体新生儿肺动脉显示，激动剂诱导的力量发展减少，内皮依赖性和非依赖性舒张增强，这可能是通过增加硝酸盐来实现的。然而，我们在接受 FeTPPS 的暴露于空气的动物中观察到内皮功能障碍、肺组织磷酸二酯酶 5 活性增强和双心室心肌肥厚。此外，与 PASMC 相比，FeTPPS 增强了新生心肌细胞的存活率。我们得出结论，用 FeTPPS 分解 ONOO(-) 可减轻慢性缺氧引起的肺动脉高压；然而，它可能会对正常肺动脉舒张功能、细胞存活和生长的调节产生负面影响。 (C) 2010 Elsevier Inc. 保留所有权利。
Evidence implicates oxidative stress as playing a prominent role in the pathogenesis of pulmonary hypertension, to which peroxynitrite anion (ONOO(-)) may make a major contribution. Hypothesizing that removal of ONOO(-) would attenuate chronic neonatal pulmonary hypertension, we examined the effects of a ONOO(-) decomposition catalyst (FeTPPS) on pulmonary arteries in vitro, on primary cultured pulmonary artery smooth muscle cell (PASMC) and cardiomyocyte survival and growth, and on central hemodynamics in rat pups exposed to hypoxia (13% O(2)) for 7 days from birth. Daily FeTPPS (30 mg/kg ip) reduced lung nitrotyrosine content, attenuated vascular remodeling, and normalized pulmonary vascular resistance in hypoxia-exposed animals. FeTPPS attenuated proliferation and increased apoptosis of neonatal PASMCs in vitro. Isolated neonatal pulmonary arteries treated with FeTPPS showed reduced agonist-induced force development and enhanced endothelium-dependent and -independent relaxation, possibly via increased nitrate. However, we observed endothelial dysfunction, enhanced lung tissue phosphodiesterase 5 activity, and biventricular cardiac hypertrophy in air-exposed animals receiving FeTPPS. Further, in contrast to PASMCs, FeTPPS enhanced survival of newborn cardiomyocytes. We conclude that decomposition of ONOO(-) with FeTPPS attenuates chronic hypoxia-induced pulmonary hypertension; however, it may negatively influence the modulation of normal pulmonary arterial relaxation function, cell survival, and growth. (C) 2010 Elsevier Inc. All rights reserved.