O‐GlcNAcylation Mediates Glucose‐Induced Alterations in Endothelial Cell Phenotype in Human Diabetes Mellitus

Autor: Bihua Feng, Robert M. Weisbrod, Jessica L. Fetterman, Naomi M. Hamburg, Rosa Bretón-Romero, Nobuyuki Masaki, Elica Inagaki
Rok vydání: 2020
Předmět:
Adult
Male
medicine.medical_specialty
Glycosylation
endocrine system diseases
Nitric Oxide Synthase Type III
030204 cardiovascular system & hematology
Vascular Medicine
O glcnacylation
03 medical and health sciences
0302 clinical medicine
Insulin resistance
Vascular Biology
insulin resistance
Internal medicine
Diabetes mellitus
medicine
Humans
Insulin
Phosphorylation
Cells
Cultured
Original Research
030304 developmental biology
endothelial nitric oxide synthase
0303 health sciences
business.industry
Endothelial Cells
Type 2 Diabetes Mellitus
Middle Aged
medicine.disease
Phenotype
beta-N-Acetylhexosaminidases
Endothelial stem cell
Forearm
Glucose
Metabolism
Endocrinology
Diabetes Mellitus
Type 2
Case-Control Studies
diabetes mellitus
High glucose
Female
Cardiology and Cardiovascular Medicine
business
Protein Processing
Post-Translational
O‐GlcNAc
Function (biology)
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
DOI: 10.1161/jaha.119.014046
Popis: Background Posttranslational protein modification with O‐linked N ‐acetylglucosamine (O‐Glc NA c) is linked to high glucose levels in type 2 diabetes mellitus (T2 DM ) and may alter cellular function. We sought to elucidate the involvement of O‐Glc NA c modification in endothelial dysfunction in patients with T2 DM . Methods and Results Freshly isolated endothelial cells obtained by J‐wire biopsy from a forearm vein of patients with T2 DM (n=18) was compared with controls (n=10). Endothelial O‐Glc NA c levels were 1.8‐ford higher in T2 DM patients than in nondiabetic controls ( P =0.003). Higher endothelial O‐Glc NA c levels correlated with serum fasting blood glucose level ( r =0.433, P =0.024) and hemoglobin A 1c ( r =0.418, P =0.042). In endothelial cells from patients with T2 DM , normal glucose conditions (24 hours at 5 mmol/L) lowered O‐Glc NA c levels and restored insulin‐mediated activation of endothelial nitric oxide synthase, whereas high glucose conditions (30 mmol/L) maintained both O‐Glc NA c levels and impaired insulin action. Treatment of endothelial cells with Thiamet G, an O‐Glc NA case inhibitor, increased O‐Glc NA c levels and blunted the improvement of insulin‐mediated endothelial nitric oxide synthase phosphorylation by glucose normalization. Conclusions Taken together, our findings indicate a role for O‐Glc NA c modification in the dynamic, glucose‐induced impairment of endothelial nitric oxide synthase activation in endothelial cells from patients with T2 DM . O‐Glc NA c protein modification may be a treatment target for vascular dysfunction in T2 DM .
Databáze: OpenAIRE
Externí odkaz: