ArticleThe Journal of clinical investigation2001
Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site.
Article in The Journal of clinical investigation, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 338 papers.
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338 citing papers in PubMed, 878 citations in OpenAlex.
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- Hyperglycemia-Induced Endothelial Dysfunction: From Classical Pathogenetic Mechanisms to Emerging Insights into ACE2 Protective Action.International journal of molecular sciences · 2026Review
- Glutamine enhances endothelial cell survival and vasodilation by increasing glutathione to reduce oxidative stress.Physiological reports · 2026Article
- Cell-state- and compartment-dependent PI3K/Akt redox signaling in chronic kidney disease: mechanisms and translational implications.Frontiers in pharmacology · 2026Review
- Plant-based diet indices in relation to novel cardiovascular risk factors, major adverse cardiovascular events, and novel anthropometric indices in patients with type 2 diabetes.Scientific reports · 2025Article
- Inhibition of hepatic gluconeogenesis in type 2 diabetes by metformin: complementary role of nitric oxide.Medical gas research · 2025Review
- Maternal Gestational Diabetes Impairs Fetoplacental Insulin-Induced Vasodilation via AKT/eNOS Pathway and Reduces Placental Efficiency.International journal of molecular sciences · 2025Article
- Polygenic risk score and cluster-based analysis suggests links between type 2 diabetes and vascular dementia in the KARE study.Nature communications · 2025Article
- The Impact of Glycaemic Variability on Vascular Dysfunction in Diabetes.Biomolecules · 2025Review
- Piezo1 activates nitric oxide synthase in red blood cells via protein kinase C with increased activity in diabetes.Mechanobiology in medicine · 2025Article
- Molecular and Immunomodulatory Mechanisms of Statins in Inflammation and Cancer Therapeutics with Emphasis on the NF-κB, NLRP3 Inflammasome, and Cytokine Regulatory Axes.International journal of molecular sciences · 2025Review
- The β-1,4 GalT-V Interactome-Potential Therapeutic Targets and a Network of Pathways Driving Cancer and Cardiovascular and Inflammatory Diseases.International journal of molecular sciences · 2025Review
- Effects of safranal on antidiabetic and endothelial dysfunction in streptozotocin-induced diabetic rats.Molecular biology reports · 2025Article
- Role of Residual Inflammation as a Risk Factor Across Cardiovascular-Kidney-Metabolic (CKM) Syndrome: Unpacking the Burden in People with Type 2 Diabetes.Diabetes therapy : research, treatment and education of diabetes and related disorders · 2025Review
- The status of studies on the mechanism of microcirculatory dysfunction in the process of diabetic kidney injury.Diabetology & metabolic syndrome · 2025Review
- The perspective of modern transplant science - transplant arteriosclerosis: inspiration derived from mitochondria associated endoplasmic reticulum membrane dysfunction in arterial diseases.International journal of surgery (London, England) · 2025Review
- PFKFB3 Connects Glycolytic Metabolism with Endothelial Dysfunction in Human and Rodent Obesity.Antioxidants (Basel, Switzerland) · 2025Article
- O-linked β-N-acetylglucosamine modification in diabetic foot ulcer pathogenesis.Burns & trauma · 2025Review
278 more citing papers are in PubMed but not listed here.
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6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Endothelial nitric oxide synthase (eNOS) is activated by phosphorylation of serine 1177 by the protein kinase Akt/PKB. Since hyperglycemia-induced mitochondrial superoxide overproduction increases O-linked N-acetylglucosamine modification and decreases O-linked phosphorylation of the transcription factor Sp1, the effect of hyperglycemia and the hexosamine pathway on eNOS was evaluated. In bovine aortic endothelial cells, hyperglycemia inhibited eNOS activity 67%, and treatment with glucosamine had a similar effect. Hyperglycemia-associated inhibition of eNOS was accompanied by a twofold increase in O-linked N-acetylglucosamine modification of eNOS and a reciprocal decrease in O-linked serine phosphorylation at residue 1177. Both the inhibition of eNOS and the changes in its post-translational modifications were reversed by antisense inhibition of glutamine:fructose-6-phosphate amidotransferase, the rate-limiting enzyme of the hexosamine pathway, or by blocking mitochondrial superoxide overproduction with uncoupling protein-1 (UCP-1) or manganese superoxide dismutase (MnSOD). Immunoblot analysis of cells expressing myc-tagged wild-type human eNOS confirmed the reciprocal increase in O-linked N-acetylglucosamine and decrease in O-linked serine 1177 phosphorylation in response to hyperglycemia. In contrast, when myc-tagged human eNOS carried a mutation at the Akt phosphorylation site (Ser1177), O-linked N-acetylglucosamine modification was unchanged by hyperglycemia and phospho-eNOS was undetectable. Similar changes in eNOS activity and covalent modification were found in aortae from diabetic animals. Chronic impairment of eNOS activity by this mechanism may partly explain the accelerated atherosclerosis of diabetes.
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