Iida Shinichiro, Chu Yi, Francis Joseph, Weiss Robert M, Gunnett Carol A, Faraci Frank M, Heistad Donald D
Cardiovascular Center and Dept. of Internal Medicine, Univ. of Iowa Roy J. and Lucille A Carver, College of Medicine, Iowa City, IA 52242, USA.
Am J Physiol Heart Circ Physiol. 2005 Aug;289(2):H525-32. doi: 10.1152/ajpheart.00108.2005.
Oxidative stress is associated with endothelial dysfunction in heart failure. The goals of this study were to determine whether 1) gene transfer of extracellular superoxide dismutase (ecSOD) reduces levels of superoxide and improves endothelial function in the aorta and mesenteric artery in rats with heart failure, and 2) the heparin-binding domain (HBD) of ecSOD, by which ecSOD binds to cells, is required for protective effects of ecSOD. Seven weeks after coronary ligation, in rats with heart failure and sham-operated rats, we injected adenoviral vectors intravenously that express ecSOD, ecSOD with deletion of the HBD (ecSODDeltaHBD), or a control vector. Four days after injection of viruses, responses to acetylcholine, ADP, and sodium nitroprusside were examined in rings of the aorta and mesenteric artery. ecSOD bound to endothelium and increased SOD activity in the aorta after gene transfer of ecSOD, not ecSODDeltaHBD. Gene transfer of ecSOD, but not ecSODDeltaHBD, reduced levels of superoxide and improved relaxation to acetylcholine and ADP in the aorta and mesenteric artery from rats with heart failure. Improvement of relaxation to acetylcholine in the mesenteric artery from rats with heart failure after gene transfer of ecSOD was mediated in part by hydrogen peroxide. The major finding of this study is that the HBD of ecSOD is necessary for protection against endothelial dysfunction in rats with heart failure. We speculate that a common gene variant in the HBD of ecSOD, which is a risk factor for ischemic heart disease, may be a risk factor for vascular maladaptation and endothelial dysfunction in heart failure.
氧化应激与心力衰竭时的内皮功能障碍有关。本研究的目的是确定：1）细胞外超氧化物歧化酶（ecSOD）的基因转移是否能降低超氧化物水平并改善心力衰竭大鼠主动脉和肠系膜动脉的内皮功能；2）ecSOD与细胞结合的肝素结合域（HBD）对于ecSOD的保护作用是否必要。冠状动脉结扎7周后，在心力衰竭大鼠和假手术大鼠中，静脉注射表达ecSOD、缺失HBD的ecSOD（ecSODDeltaHBD）或对照载体的腺病毒载体。注射病毒4天后，检测主动脉和肠系膜动脉环对乙酰胆碱、ADP和硝普钠的反应。ecSOD基因转移后，ecSOD而非ecSODDeltaHBD与内皮结合并增加主动脉中的SOD活性。ecSOD而非ecSODDeltaHBD的基因转移降低了心力衰竭大鼠主动脉和肠系膜动脉中的超氧化物水平，并改善了对乙酰胆碱和ADP的舒张反应。ecSOD基因转移后，心力衰竭大鼠肠系膜动脉对乙酰胆碱舒张反应的改善部分由过氧化氢介导。本研究的主要发现是，ecSOD的HBD对于预防心力衰竭大鼠的内皮功能障碍是必要的。我们推测，ecSOD的HBD中的一个常见基因变异是缺血性心脏病的危险因素，它可能是心力衰竭时血管适应不良和内皮功能障碍的危险因素。
