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

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 gly...

Full description

Saved in:
Bibliographic Details
Published in:Microvascular research Vol. 146; p. 104468
Main Authors: He, An, Guo, Yongzheng, Xu, Zhixin, Yan, Jianghong, Xie, Lingyun, Li, Yuanjing, Lv, Dingyi, Luo, Minghao
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01.03.2023
Subjects:
Animals
Diabetes
Diabetes Mellitus, Experimental
Endothelial-dependent vasodilation
Endothelium, Vascular - metabolism
eNOS
Hypoglycaemia
Hypoglycemia
iNOS
Insulins - metabolism
Insulins - pharmacology
Insulins - therapeutic use
Nitric Oxide - metabolism
Nitric Oxide Synthase Type II - metabolism
Nitric Oxide Synthase Type III - metabolism
Oxidative stress
Phosphorylation
Post-translation modifications
Rats
Rats, Sprague-Dawley
Vascular Diseases
Vasodilation
Oxidative stress
eNOS
Post-translation modifications
Hypoglycaemia
iNOS
Diabetes
Endothelial-dependent vasodilation
ISSN:0026-2862, 1095-9319, 1095-9319
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. 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. 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 phosphorylation of Akt at Ser-473, and increased protein kinase C α subunit (PKCα). iNOS expression was induced in hypoglycaemia. Furthermore, endothelial-dependent vasodilation was impaired under insulin-induced hypoglycaemia, and further in recurrent hypoglycaemia. 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. •Our study findings demonstrate that diabetic hypoglycaemia-related endothelium dysfunction is associated with hypoglycaemia-induced increase in eNOS O-GlcNAcylation and Thr-495 phosphorylation, and decreased eNOS-Ser 1177 phosphorylation in the arteries.•Increased O-GlcNAc modification and Thr-495 phosphorylation, and decreased Ser-1177 phosphorylation of eNOS, were positively mediated by OGT and PKCα and negatively mediated by phosphorylation of Akt at Ser-473, respectively, in diabetes under hypoglycaemia.•This study is the first to report on the effect of hypoglycaemia on increased iNOS expression in normal SD rats, which may cause oxidative stress in thoracic aortas and mesenteric arteries in diabetes.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0026-2862
1095-9319
1095-9319
DOI:10.1016/j.mvr.2022.104468