Thum Thomas, Fraccarollo Daniela, Schultheiss Maximilian, Froese Sabrina, Galuppo Paolo, Widder Julian D, Tsikas Dimitrios, Ertl Georg, Bauersachs Johann
Universitatsklinikum, Medizinische Klinik I, Universität Würzburg, Josef-Schneider Strasse 2, 97080 Würzburg, Germany.
Diabetes. 2007 Mar;56(3):666-74. doi: 10.2337/db06-0699.
Uncoupling of the endothelial nitric oxide synthase (eNOS) resulting in superoxide anion (O(2)(-)) formation instead of nitric oxide (NO) causes diabetic endothelial dysfunction. eNOS regulates mobilization and function of endothelial progenitor cells (EPCs), key regulators of vascular repair. We postulate a role of eNOS uncoupling for reduced number and function of EPC in diabetes. EPC levels in diabetic patients were significantly reduced compared with those of control subjects. EPCs from diabetic patients produced excessive O(2)(-) and showed impaired migratory capacity compared with nondiabetic control subjects. NOS inhibition with N(G)-nitro-l-arginine attenuated O(2)(-) production and normalized functional capacity of EPCs from diabetic patients. Glucose-mediated EPC dysfunction was protein kinase C dependent, associated with reduced intracellular BH(4) (tetrahydrobiopterin) concentrations, and reversible after exogenous BH(4) treatment. Activation of NADPH oxidases played an additional but minor role in glucose-mediated EPC dysfunction. In rats with streptozotocin-induced diabetes, circulating EPCs were reduced to 39 +/- 5% of controls and associated with uncoupled eNOS in bone marrow. Our results identify uncoupling of eNOS in diabetic bone marrow, glucose-treated EPCs, and EPCs from diabetic patients resulting in eNOS-mediated O(2)(-) production. Subsequent reduction of EPC levels and impairment of EPC function likely contributes to the pathogenesis of vascular disease in diabetes.
内皮型一氧化氮合酶（eNOS）解偶联导致超氧阴离子（O₂⁻）生成而非一氧化氮（NO），从而引发糖尿病性内皮功能障碍。eNOS调节内皮祖细胞（EPCs）的动员和功能，而EPCs是血管修复的关键调节因子。我们推测eNOS解偶联在糖尿病中EPC数量减少和功能降低方面发挥作用。与对照组相比，糖尿病患者的EPC水平显著降低。与非糖尿病对照组相比，糖尿病患者的EPC产生过量的O₂⁻，且迁移能力受损。用N⁎-硝基-L-精氨酸抑制一氧化氮合酶可减弱糖尿病患者EPC的O₂⁻生成，并使其功能能力恢复正常。葡萄糖介导的EPC功能障碍依赖蛋白激酶C，与细胞内四氢生物蝶呤（BH₄）浓度降低有关，外源性BH₄治疗后可逆转。NADPH氧化酶的激活在葡萄糖介导的EPC功能障碍中起额外但较小的作用。在链脲佐菌素诱导的糖尿病大鼠中，循环EPCs减少至对照组的39±5%，并与骨髓中eNOS解偶联有关。我们的研究结果表明，糖尿病骨髓、葡萄糖处理的EPCs以及糖尿病患者的EPCs中eNOS解偶联导致eNOS介导的O₂⁻生成。随后EPC水平降低和EPC功能受损可能促成糖尿病血管疾病的发病机制。
