Hypoglycaemia aggravates impaired endothelial-dependent vasodilation in diabetes by suppressing endothelial nitric oxide synthase activity and stimulating inducible nitric oxide synthase expression

作者全名："He, An; Guo, Yongzheng; Xu, Zhixin; Yan, Jianghong; Xie, Lingyun; Li, Yuanjing; Lv, Dingyi; Luo, Minghao"

作者地址："[He, An; Guo, Yongzheng; Xu, Zhixin; Xie, Lingyun; Li, Yuanjing; Lv, Dingyi; Luo, Minghao] Chongqing Med Univ, Div Cardiol, Affiliated Hosp 1, Chongqing, Peoples R China; [Yan, Jianghong] Chongqing Med Univ, Inst Life Sci, Chongqing, Peoples R China"

通信作者："Lv, DY; Luo, MH (通讯作者)，Chongqing Med Univ, Div Cardiol, Affiliated Hosp 1, Chongqing, Peoples R China."

来源：MICROVASCULAR RESEARCH

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000909823800001

JCR分区：Q2

影响因子：2.9

年份：2023

卷号：146

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Hypoglycaemia; Diabetes; eNOS; Post-translation modifications; iNOS; Oxidative stress; Endothelial-dependent vasodilation

摘要："Background: Diabetes exacerbates vascular injury by triggering endothelial dysfunction. Endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) both play major roles in endothelial dysfunction. However, effects of hypoglycaemia, the main complication of the insulin therapy to the glycemic control in diabetes, on eNOS activity and iNOS expression, and underlying mechanisms in diabetes remain unknown. Hence, we aimed to determine the effects of hypoglycaemia on eNOS activity and iNOS expression in different arterial beds of diabetic rats.Methods: Sprague-Dawley rats were subjected to Streptozotocin (STZ) combined with high fat diet (HFD) to induce diabetes and then received insulin injection to attain acute and recurrent hypoglycaemia. Immunoblotting was used to analyse the phosphorylation and O-glycosylation status of eNOS and iNOS level from thoracic aorta and mesenteric artery tissue. Indicators of oxidative stress from plasm were determined, and endothelial-dependent vasodilation was detected via wire myograph system. Results: Hypoglycaemia was associated with a marked increase in eNOS O-GlcNAcylation and decrease in Serine (Ser)-1177 phosphorylation from thoracic aortas and mesenteric arteries. Moreover, hypoglycaemia resulted in elevated phosphorylation of eNOS at Threonine (Thr)-495 site in mesenteric arteries. Besides, changes in these post-translational modifications were associated with increased O-GlcNAc transferase (OGT), decreased phos-phorylation of Akt at Ser-473, and increased protein kinase C alpha subunit (PKC alpha). iNOS expression was induced in hypoglycaemia. Furthermore, endothelial-dependent vasodilation was impaired under insulin-induced hypo-glycaemia, and further in recurrent hypoglycaemia.Conclusions: Conclusively, these findings strongly indicate that hypoglycaemia-dependent vascular dysfunction in diabetes is mediated through altered eNOS activity and iNOS expression. Therefore, this implies that therapeutic modulation of eNOS activity and iNOS expression in diabetics under intensive glucose control may prevent and treat adverse cardiovascular events."

基金机构："Natural Science Foundation of Chongqing, China; project of Innovation Program for Doctoral Student of The First Affiliated Hospital of Chongqing Medical University; [2022NSCQ-MSX1372]; [CYYY-BSYJSCXXM-202202]"

基金资助正文："Funding This work was sponsored by Natural Science Foundation of Chongqing, China (2022NSCQ-MSX1372) and the project of Innovation Program for Doctoral Student of The First Affiliated Hospital of Chongqing Medical University (CYYY-BSYJSCXXM-202202) ."