Department of Physiology, New York Medical College, Valhalla, New York, USA.
Diabetes. 2012 Dec;61(12):3181-8. doi: 10.2337/db12-0559. Epub 2012 Aug 28.
We aimed to investigate specific roles of mitogen-activated protein kinases (MAPK) in the deterioration of endothelial function during the progression of diabetes and the potential therapeutic effects of MAPK inhibitors and agonists in the amelioration of endothelial function. Protein expression and phosphorylation of p38, c-Jun NH(2)-terminal kinase (JNK), and extracellular signal-regulated kinase (Erk) were assessed in mesenteric arteries of 3- (3M) and 9-month-old (9M) male diabetic and control mice. The expression of p38, JNK, and Erk was comparable in all groups of mice, but the phosphorylation of p38 and JNK was increased in 3M and further increased in 9M diabetic mice, whereas the phosphorylation of Erk was substantially reduced in 9M diabetic mice. NADPH oxidase-dependent superoxide production was significantly increased in vessels of two ages of diabetic mice. Inhibition of either p38 with SB203580 or JNK with SP600125 reduced superoxide production and improved shear stress-induced dilation (SSID) in 3M, but not in 9M, diabetic mice. Treating the vessels of 9M diabetic mice with resveratrol increased Erk phosphorylation and shear stress-induced endothelial nitric oxide synthase (eNOS) phosphorylation and activity, but resveratrol alone did not improve SSID. Administration of resveratrol and SB203580 or resveratrol and SP600125 together significantly improved SSID in vessels of 9M diabetic mice. The improved response was prevented by U0126, an Erk inhibitor. Thus, p38/JNK-dependent increase in oxidative stress diminished nitric oxide-mediated dilation in vessels of 3M diabetic mice. Oxidative stress and impaired Erk-dependent activation of eNOS exacerbates endothelial dysfunction in the advanced stage of diabetes.
我们旨在研究丝裂原活化蛋白激酶（MAPK）在糖尿病进展过程中内皮功能恶化中的特定作用，以及 MAPK 抑制剂和激动剂在改善内皮功能方面的潜在治疗效果。在 3 个月（3M）和 9 个月（9M）龄雄性糖尿病和对照小鼠的肠系膜动脉中评估了 p38、c-Jun NH(2)-末端激酶（JNK）和细胞外信号调节激酶（Erk）的蛋白表达和磷酸化。在所有组别的小鼠中，p38、JNK 和 Erk 的表达都相当，但 p38 和 JNK 的磷酸化在 3M 时增加，在 9M 糖尿病小鼠中进一步增加，而 Erk 的磷酸化在 9M 糖尿病小鼠中显著降低。NADPH 氧化酶依赖性超氧化物的产生在两个年龄的糖尿病小鼠的血管中显著增加。用 SB203580 抑制 p38 或用 SP600125 抑制 JNK 减少了 3M 但不是 9M 糖尿病小鼠中血管的超氧化物产生和切应力诱导的舒张（SSID）。用白藜芦醇处理 9M 糖尿病小鼠的血管增加了 Erk 磷酸化和切应力诱导的内皮型一氧化氮合酶（eNOS）磷酸化和活性，但白藜芦醇本身并没有改善 SSID。白藜芦醇和 SB203580 或白藜芦醇和 SP600125 联合给药显著改善了 9M 糖尿病小鼠血管中的 SSID。用 Erk 抑制剂 U0126 阻止了这种改善反应。因此，p38/JNK 依赖性氧化应激增加减弱了 3M 糖尿病小鼠血管中一氧化氮介导的舒张。氧化应激和 Erk 依赖性激活 eNOS 受损加剧了糖尿病晚期的内皮功能障碍。
