Decreases in manganese superoxide dismutase expression and activity contribute to oxidative stress in persistent pulmonary hypertension of the newborn
Decreases in manganese superoxide dismutase expression and activity contribute to oxidative stress in persistent pulmonary hypertension of the newborn
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DOI：
10.1152/ajplung.00098.2012
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发表时间：
2012-11-01
影响因子：
4.9
通讯作者：
Konduri, Girija G.
中科院分区：
文献类型：
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作者：
Afolayan, Adeleye J.;Eis, Annie;Konduri, Girija G.
Afolayan AJ，Eis A，Teng R，Bakhutashvili I，Kaul S，Davis JM，Konduri GG.锰超氧化物歧化酶表达和活性的降低有助于新生儿持续性肺动脉高压的氧化应激美国生理学杂志肺细胞分子生理学303：L 870-L 879，2012年。首次发表于2012年9月7日; doi：10.1152/ajplung.00098.2012.-一氧化氮（NO）的合成和释放的快速增加促进了出生相关过渡期间发生的肺血管舒张。新生儿持续性肺动脉高压（PPHN）中这种转变的改变与内皮型一氧化氮合酶（eNOS）功能受损和氧化应激增加有关。我们研究了这一假设，即在肺动脉内皮细胞（PAEC）的线粒体局部锰超氧化物歧化酶（MnSOD）的表达和活性的降低，增加氧化应激和损害eNOS功能的PPHN。我们从产前动脉导管结扎或假结扎（对照）诱导的PPHN胎羊中分离PAEC和肺动脉。我们研究了MnSOD的表达和活性，酪氨酸硝化MnSOD，和线粒体O-2（-）水平在PAEC从对照组和PPHN羔羊。我们通过腺病毒载体（ad-MnSOD）将外源性MnSOD导入PPHN羔羊的PAEC和肺动脉。观察ad-MnSOD对PAEC线粒体O-2（-）水平、MnSOD和eNOS表达和活性、细胞内过氧化氢（H2 O2）水平和过氧化氢酶表达的影响。PPHN-PAEC中MnSOD mRNA和蛋白水平及活性降低，MnSOD酪氨酸硝化增加。PPHN-PAEC的ad-MnSOD转导使其活性增加2 - 3倍，降低线粒体O-2（-）水平，并增加H2 O2水平和过氧化氢酶表达。ad-MnSOD基因转导可增强PPHN肺动脉内皮型一氧化氮合酶（eNOS）的表达和功能，改善PPHN肺动脉舒张反应。我们的观察结果表明，MnSOD的表达和活性降低有助于在PPHN中观察到的内皮功能障碍。
Afolayan AJ, Eis A, Teng R, Bakhutashvili I, Kaul S, Davis JM, Konduri GG. Decreases in manganese superoxide dismutase expression and activity contribute to oxidative stress in persistent pulmonary hypertension of the newborn. Am J Physiol Lung Cell Mol Physiol 303: L870-L879, 2012. First published September 7, 2012; doi:10.1152/ajplung.00098.2012.-A rapid increase in the synthesis and release of nitric oxide (NO) facilitates the pulmonary vasodilation that occurs during birth-related transition. Alteration of this transition in persistent pulmonary hypertension of the newborn (PPHN) is associated with impaired function of endothelial nitric oxide synthase (eNOS) and an increase in oxidative stress. We investigated the hypothesis that a decrease in expression and activity of mitochondrial localized manganese superoxide dismutase (MnSOD) in pulmonary artery endothelial cells (PAEC) increases oxidative stress and impairs eNOS function in PPHN. We isolated PAEC and pulmonary arteries from fetal lambs with PPHN induced by prenatal ductus arteriosus ligation or sham ligation (control). We investigated MnSOD expression and activity, tyrosine nitration of MnSOD, and mitochondrial O-2(-) levels in PAEC from control and PPHN lambs. We introduced exogenous MnSOD via an adenoviral vector (ad-MnSOD) transduction into PAEC and pulmonary arteries of PPHN lambs. The effect of ad-MnSOD was investigated on: mitochondrial O-2(-) levels, MnSOD and eNOS expression and activity, intracellular hydrogen peroxide (H2O2) levels, and catalase expression in PAEC. MnSOD mRNA and protein levels and activity were decreased and MnSOD tyrosine nitration was increased in PPHN-PAEC. ad-MnSOD transduction of PPHN-PAEC increased its activity two- to threefold, decreased mitochondrial O-2(-) levels, and increased H2O2 levels and catalase expression. ad-MnSOD transduction improved eNOS expression and function and the relaxation response of PPHN pulmonary arteries. Our observations suggest that decreased MnSOD expression and activity contribute to the endothelial dysfunction observed in PPHN.