Vascular effects of a common gene variant of extracellular superoxide dismutase in heart failure
Vascular effects of a common gene variant of extracellular superoxide dismutase in heart failure
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DOI：
10.1152/ajpheart.00080.2006
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发表时间：
2006-08-01
影响因子：
4.8
通讯作者：
Heistad, Donald D.
中科院分区：
文献类型：
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作者：
Iida, Shinichiro;Weiss, Robert M.;Heistad, Donald D.
人类细胞外超氧化物歧化酶（ecSOD）的一种常见基因变异与缺血性心脏病的风险增加有关，约占人类总数的5%。本研究的目的是研究ecSOD对心力衰竭大鼠血管的影响以及ecSOD变体（ecSOD(R213G)）的影响。冠状动脉结扎7周后，我们研究了心力衰竭大鼠和假手术大鼠。静脉注射表达人ecSOD、ecSOD（R213G）或对照病毒的腺病毒载体。在心力衰竭大鼠的主动脉中，乙酰胆碱（69 +/- 4%松弛，平均+/- SE）和一氧化氮（NO）的基础水平（对NO合成酶抑制剂的血管收缩反应）大大受损，超氧化物和过氧亚硝酸盐水平升高。ecSOD的基因转移使心力衰竭大鼠主动脉对乙酰胆碱（92 +/- 2%松弛）和基础一氧化氮水平的反应恢复到正常水平，超氧化物水平[从2.3 +/- 0.2到0.9 +/- 0.2相对光单位每秒每平方毫米(RLU (.) s(-1) (.) mm(-2)]和过氧亚硝酸盐(从2.4 +/- 0.2到0.9 +/- 0.1 RLU (.) s(-1) (.) mm(-2))]降低。基因转移对ecSOD（R213G）几乎没有改善。对硝普塞的反应各组间无差异。各组主动脉内源性sod （CuZnSOD、MnSOD和ecSOD）和内皮NOS mRNA的表达无显著差异。与ecSOD相比，ecSOD（R213G）在心力衰竭大鼠体内的基因转移对氧化应激、内皮功能或一氧化氮的基础生物利用度的有益影响微乎其微。我们推测，ecSOD（R213G）对氧化应激和内皮功能障碍的保护作用大大降低可能导致ecSOD（R213G）患者心血管疾病的风险增加。
A common gene variant of human extracellular superoxide dismutase (ecSOD), in similar to 5% of humans, is associated with increased risk of ischemic heart disease. The purpose of this study was to examine vascular effects of ecSOD with effects of the ecSOD variant (ecSOD(R213G)) in rats with heart failure. Seven weeks after coronary artery ligation, we studied rats with heart failure and sham-operated rats. Adenoviral vectors expressing human ecSOD, ecSOD(R213G), or a control virus were injected intravenously. In the aorta from rats with heart failure, responses to acetylcholine (69 +/- 4% relaxation, means +/- SE) and basal levels of nitric oxide (NO) (vasoconstrictor responses to a NO synthase inhibitor) were greatly impaired, and levels of superoxide and peroxynitrite were increased. Gene transfer of ecSOD restored responses to acetylcholine (92 +/- 2% relaxation) and basal levels of NO to normal and reduced levels of superoxide [from 2.3 +/- 0.2 to 0.9 +/- 0.2 relative light units per second per millimeter squared (RLU (.) s(-1) (.) mm(-2))] and peroxynitrite (from 2.4 +/- 0.2 to 0.9 +/- 0.1 RLU (.) s(-1) (.) mm(-2)) in the aorta from rats with heart failure. Gene transfer of ecSOD(R213G) produced little or no improvement. Responses to nitroprusside were not different among the groups. Expression of endogenous mRNA for SODs (CuZnSOD, MnSOD, and ecSOD) and endothelial NOS in the aorta was not different among the groups. In contrast to ecSOD, gene transfer of ecSOD(R213G) in rats with heart failure has minimal beneficial effect on oxidative stress, endothelial function, or basal bioavailability of NO. We speculate that greatly diminished efficacy of ecSOD(R213G) in protection against oxidative stress and endothelial dysfunction may contribute to increased risk of cardiovascular disease in humans with ecSOD(R213G).