期刊
JOURNAL OF THE AMERICAN HEART ASSOCIATION
卷 9, 期 12, 页码 -出版社
WILEY
DOI: 10.1161/JAHA.119.014046
关键词
diabetes mellitus; endothelial nitric oxide synthase; insulin resistance; O-GlcNAc
资金
- National Heart, Lung, and Blood Institute [HL081587, HL115391, HL102299]
- AHA SDG
- Ministry of Education, Science, and Culture of Japan [17K09565]
- [KO1 HL143142]
- Grants-in-Aid for Scientific Research [17K09565] Funding Source: KAKEN
BACKGROUND: Posttranslational protein modification with O-linked N-acetylglucosamine (O-GlcNAc) is linked to high glucose levels in type 2 diabetes mellitus (T2DM) and may alter cellular function. We sought to elucidate the involvement of O-GlcNAc modification in endothelial dysfunction in patients with T2DM. METHODS AND RESULTS: Freshly isolated endothelial cells obtained by J-wire biopsy from a forearm vein of patients with T2DM (n=18) was compared with controls (n=10). Endothelial O-GlcNAc levels were 1.8-ford higher in T2DM patients than in nondiabetic controls (P=0.003). Higher endothelial O-GlcNAc 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 T2DM, normal glucose conditions (24 hours at 5 mmol/L) lowered O-GlcNAc levels and restored insulin-mediated activation of endothelial nitric oxide synthase, whereas high glucose conditions (30 mmol/L) maintained both O-GlcNAc levels and impaired insulin action. Treatment of endothelial cells with Thiamet G, an O-GlcNAcase inhibitor, increased O-GlcNAc 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-GlcNAc modification in the dynamic, glucose-induced impairment of endothelial nitric oxide synthase activation in endothelial cells from patients with T2DM. O-GlcNAc protein modification may be a treatment target for vascular dysfunction in T2DM.
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