Mechanisms of increased vascular superoxide production in human diabetes mellitus Role of NAD(P)H oxidase and endothelial nitric oxide synthase
Mechanisms of increased vascular superoxide production in human diabetes mellitus Role of NAD(P)H oxidase and endothelial nitric oxide synthase
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DOI：
10.1161/01.cir.0000012748.58444.08
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发表时间：
2002-04-09
期刊：
影响因子：
37.8
通讯作者：
Channon, KM
中科院分区：
文献类型：
--
作者：
Guzik, TJ;Mussa, S;Channon, KM
背景：在糖尿病实验模型中，超氧化物的产生增加导致血管一氧化氮（NO）生物活性降低和内皮功能障碍。我们比较了糖尿病合并冠状动脉疾病患者与非糖尿病患者血管超氧化物产生的来源和机制。方法与结果：对45例接受冠状动脉搭桥手术的糖尿病患者和45例相应的非糖尿病患者的隐静脉和乳腺内动脉血管超氧化物生成进行了定量分析。NAD(P)H依赖性氧化酶是糖尿病和非糖尿病患者血管超氧化物的重要来源，但该酶系统的活性和NAD(P)H氧化酶蛋白亚基（p22phox、p67phox和p47phox）的水平在糖尿病静脉和动脉中均显著升高。在非糖尿病血管中，内皮NO合酶产生清除超氧化物的NO。然而，在糖尿病血管中，内皮是产生超氧化物的额外净来源，因为内皮NO合成酶功能失调，细胞内补充四氢生物蝶呤可以纠正这一现象。此外，增加的超氧化物产生在糖尿病是由蛋白激酶C抑制剂chelerythrine取消。结论：这些观察结果提示NAD(P)H氧化酶、内皮NO合酶解偶联和蛋白激酶C信号在介导糖尿病血管超氧化物生成增加和内皮功能障碍中的重要作用。
Background-Increased superoxide production contributes to reduced vascular nitric oxide (NO) bioactivity and endothelial dysfunction in experimental models of diabetes. We characterized the Sources and mechanisms underlying vascular superoxide production in human blood vessels from diabetic patients with coronary artery disease compared with nondiabetic patients.Methods and Results-Vascular superoxide production was quantified in both saphenous veins and internal mammary arteries from 45 diabetic and 45 matched nondiabetic patients undergoing coronary artery bypass surgery. NAD(P)H-dependent oxidases were important sources of vascular superoxide in both diabetic and nondiabetic patients, but both the activity of this enzyme system and the levels of NAD(P)H oxidase protein subunits (p22phox, p67phox, and p47phox) were significantly increased in diabetic veins and arteries. In nondiabetic vessels, endothelial NO synthase produced NO that scavenged superoxide. However, in diabetic vessels, the endothelium was an additional net source of superoxide production because of dysfunctional endothelial NO synthase that was corrected by intracellular tetrahydrobiopterin supplementation. Furthermore, increased superoxide production in diabetes was abrogated by the protein kinase C inhibitor chelerythrine.Conclusions-These observations suggest important roles for NAD(P)H oxidases, endothelial NO synthase uncoupling and protein kinase C signaling in mediating increased vascular superoxide production and endothelial dysfunction in human diabetes mellitus.