Ahmad M, Turkseven S, Mingone C J, Gupte S A, Wolin M S, Abraham N G
Department of Physiology, New York Medical College, Valhalla, New York 10595, USA.
Cell Mol Biol (Noisy-le-grand). 2005 Sep 30;51(4):371-6.
Hyperglycemia represents the main cause of complication of diabetes mellitus and oxidative stress, resulting from increased generation of reactive oxygen species (ROS), and plays a crucial role in their pathogenesis. Impairment of vascular responses in diabetic rats, as a result of an increase in superoxide (O2-), formation is a major complication in diabetes. Since heme oxygenase (HO) expression regulates the level of ROS by increasing antioxidant, such as glutathione and bilirubin, we investigated whether upregulation of HO-1 modulates the levels of iNOS and eNOS and altered vascular responses to phenylephrine (PE) and acetylcholine (Ach) in aorta and femoral arteries of diabetic (streptozotocin (STZ)-induced) rats. Our results showed that iNOS expression was increased, but HO activity was reduced, in diabetic compared to nondiabetic rats (p<0.05). Upregulation of HO-1 expression by cobalt protoporphyrin (CoPP), an inducer of HO-1 protein and activity, conferred an increase in eNOS and differentially decreased iNOS protein levels (p<0.05). Isolated aortic and femoral arteries obtained from diabetic rats exhibited contraction to PE and relaxation to Ach, which were markedly increased and decreased, respectively. However, HO-1 induction in diabetic rats normalized relaxation compared to controls. Therefore, overexpression of HO-1 may mediate an increase in eNOS and a decrease in iNOS, potentially contributing to restoration of vascular responses in diabetic rats.
高血糖是糖尿病并发症的主要原因，由活性氧（ROS）生成增加导致氧化应激，在其发病机制中起关键作用。糖尿病大鼠血管反应受损，超氧化物（O2-）生成增加是糖尿病的主要并发症。由于血红素加氧酶（HO）表达通过增加抗氧化剂如谷胱甘肽和胆红素来调节ROS水平，我们研究了HO-1的上调是否会调节糖尿病（链脲佐菌素（STZ）诱导）大鼠主动脉和股动脉中诱导型一氧化氮合酶（iNOS）和内皮型一氧化氮合酶（eNOS）的水平以及改变对去氧肾上腺素（PE）和乙酰胆碱（Ach）的血管反应。我们的结果表明，与非糖尿病大鼠相比，糖尿病大鼠中iNOS表达增加，但HO活性降低（p<0.05）。HO-1蛋白和活性的诱导剂钴原卟啉（CoPP）上调HO-1表达，使eNOS增加，iNOS蛋白水平差异降低（p<0.05）。从糖尿病大鼠获得的离体主动脉和股动脉对PE表现出收缩，对Ach表现出舒张，分别显著增加和降低。然而，与对照组相比，糖尿病大鼠中HO-1的诱导使舒张恢复正常。因此，HO-1的过表达可能介导eNOS增加和iNOS减少，可能有助于恢复糖尿病大鼠的血管反应。
