Sharma Shruti, Grobe Albert C, Wiseman Dean A, Kumar Sanjiv, Englaish Manal, Najwer Ida, Benavidez Eileen, Oishi Peter, Azakie Anthony, Fineman Jeffrey R, Black Stephen M
Vascular Biology Center, Medical College of Georgia, CB3210B, 1459 Laney Walker Blvd, Augusta, GA 30912, USA.
Am J Physiol Lung Cell Mol Physiol. 2007 Oct;293(4):L960-71. doi: 10.1152/ajplung.00449.2006. Epub 2007 Jul 13.
Increasing data suggest that oxidative stress, due to an increased production of reactive oxygen species and/or a decrease in antioxidants, is involved in the pathophysiology of pulmonary hypertension. Several antioxidant systems regulate the presence of oxidant species in vivo, and of primary interest are the superoxide dismutases (SOD) and catalase. However, little is known about the expression of antioxidant enzymes during the development of pulmonary hypertension. This study uses our lamb model of increased postnatal pulmonary blood flow, secondary to in utero aortopulmonary graft placement (shunt lambs), to investigate the expression patterns as well as activities of antioxidant enzymes during the early development of pulmonary hypertension. Protein levels of catalase, SOD1, SOD2, and SOD3 were evaluated by Western blot, and the activities of catalase and SOD were also quantified. In control lambs, protein expression and activities of catalase and SOD2 increased postnatally (P < 0.05). However, SOD1 and SOD3 protein levels did not change. In shunt lambs, catalase, SOD1, and SOD2 protein levels all increased over the first 8 wk of life (P < 0.05). However, SOD3 did not change. This was associated with an increase in the activities of catalase and SOD2 (P < 0.05). Compared with control lambs, catalase and SOD2 protein levels were decreased in 2-wk-old shunt lambs and this was associated with increased levels of hydrogen peroxide (H(2)O(2)) and superoxide (P < 0.05). Developmentally superoxide but not H(2)O(2) levels significantly increased in both shunt and control lambs with levels being significantly higher in shunt compared with control lambs at 2 and 4 but not 8 wk. These data suggest that the antioxidant enzyme systems are dynamically regulated postnatally, and this regulation is altered during the development of pulmonary hypertension secondary to increased pulmonary blood flow. An increased understanding of these alterations may have important therapeutic implications for the treatment of pulmonary hypertension secondary to increased pulmonary blood flow.
越来越多的数据表明，由于活性氧生成增加和/或抗氧化剂减少导致的氧化应激参与了肺动脉高压的病理生理学过程。几种抗氧化系统调节体内氧化剂的存在，其中主要的是超氧化物歧化酶（SOD）和过氧化氢酶。然而，关于肺动脉高压发展过程中抗氧化酶的表达知之甚少。本研究利用我们的羔羊模型，即由于子宫内主动脉肺动脉分流移植（分流羔羊）导致出生后肺血流量增加，来研究肺动脉高压早期发展过程中抗氧化酶的表达模式和活性。通过蛋白质印迹法评估过氧化氢酶、SOD1、SOD2和SOD3的蛋白质水平，并对过氧化氢酶和SOD的活性进行定量。在对照羔羊中，过氧化氢酶和SOD2的蛋白质表达和活性在出生后增加（P<0.05）。然而，SOD1和SOD3的蛋白质水平没有变化。在分流羔羊中，过氧化氢酶、SOD1和SOD2的蛋白质水平在生命的前8周内均增加（P<0.05）。然而，SOD3没有变化。这与过氧化氢酶和SOD2活性的增加有关（P<0.05）。与对照羔羊相比，2周龄分流羔羊的过氧化氢酶和SOD2蛋白质水平降低，这与过氧化氢（H₂O₂）和超氧化物水平升高有关（P<0.05）。在发育过程中，分流羔羊和对照羔羊的超氧化物水平均显著增加，但H₂O₂水平没有显著增加，在2周和4周时，分流羔羊的超氧化物水平显著高于对照羔羊，但在8周时没有差异。这些数据表明，抗氧化酶系统在出生后受到动态调节，并且在由于肺血流量增加导致的肺动脉高压发展过程中这种调节发生改变。对这些改变的进一步了解可能对治疗由于肺血流量增加导致的肺动脉高压具有重要的治疗意义。
