Nie Hong, Wu Ji-Liang, Zhang Miao, Xu Jian, Zou Ming-Hui
BSEB 325, Section of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA.
Diabetes. 2006 Nov;55(11):3133-41. doi: 10.2337/db06-0505.
There is evidence that reactive nitrogen species are implicated in diabetic vascular complications, but their sources and targets remain largely unidentified. In the present study, we aimed to study the roles of endothelial nitric oxide synthase (eNOS) in diabetes. Exposure of isolated bovine coronary arteries to high glucose (30 mmol/l d-glucose) but not to osmotic control mannitol (30 mmol/l) switched angiotensin II-stimulated prostacyclin (PGI(2))-dependent relaxation into a persistent vasoconstriction that was sensitive to either indomethacin, a cyclooxygenase inhibitor, or SQ29548, a selective thromboxane receptor antagonist. In parallel, high glucose, but not mannitol, significantly increased superoxide and 3-nitrotyrosine in PGI(2) synthase (PGIS). Concurrent administration of polyethylene-glycolated superoxide dismutase (SOD), l-nitroarginine methyl ester, or sepiapterin not only reversed the effects of high glucose on both angiotensin II-induced relaxation and PGI(2) release but also abolished high-glucose-enhanced PGIS nitration, as well as its association with eNOS. Furthermore, diabetes significantly suppressed PGIS activity in parallel with increased superoxide and PGIS nitration in the aortas of diabetic C57BL6 mice but had less effect in diabetic mice either lacking eNOS or overexpressing human SOD (hSOD(+/+)), suggesting an eNOS-dependent PGIS nitration in vivo. We conclude that diabetes increases PGIS nitration in vivo, likely via dysfunctional eNOS.
有证据表明活性氮物质与糖尿病血管并发症有关，但其来源和靶点在很大程度上仍未明确。在本研究中，我们旨在探讨内皮型一氧化氮合酶（eNOS）在糖尿病中的作用。将分离的牛冠状动脉暴露于高糖（30 mmol/l d-葡萄糖）而非渗透压对照甘露醇（30 mmol/l）中，可使血管紧张素II刺激的前列环素（PGI₂）依赖性舒张转变为对环氧化酶抑制剂吲哚美辛或选择性血栓素受体拮抗剂SQ29548敏感的持续性血管收缩。同时，高糖而非甘露醇可显著增加PGI₂合酶（PGIS）中的超氧化物和3-硝基酪氨酸。同时给予聚乙二醇化超氧化物歧化酶（SOD）、L-硝基精氨酸甲酯或蝶呤不仅可逆转高糖对血管紧张素II诱导的舒张和PGI₂释放的影响，还可消除高糖增强的PGIS硝化作用及其与eNOS的关联。此外，糖尿病可显著抑制糖尿病C57BL6小鼠主动脉中的PGIS活性，同时超氧化物和PGIS硝化作用增加，但对缺乏eNOS或过表达人SOD（hSOD⁺/⁺）的糖尿病小鼠影响较小，提示体内存在eNOS依赖性的PGIS硝化作用。我们得出结论，糖尿病可能通过功能失调的eNOS增加体内PGIS硝化作用。
