Acute O-GlcNAcylation prevents inflammation-induced vascular dysfunction

作者：Hilgers Rob H P; Xing Dongqi; Gong Kaizheng; Chen Yiu Fai; Chatham John C; Oparil Suzanne^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2012, 303(5): H513-H522.

DOI：10.1152/ajpheart.01175.2011

• endothelial dysfunction
• tumor necrosis factor-alpha
• aortic ring
• rat
• D-glucosamine
• O-linked N-acetyl-glucosamine

Hilgers RH, Xing D, Gong K, Chen YF, Chatham JC, Oparil S. Acute O-GlcNAcylation prevents inflammation-induced vascular dysfunction. Am J Physiol Heart Circ Physiol 303: H513-H522, 2012. First published July 9, 2012; doi:10.1152/ajpheart.01175.2011.-Acute increases in cellular protein O-linked N-acetyl-glucosamine (O-GlcNAc) modification (O-GlcNAcylation) have been shown to have protective effects in the heart and vasculature. We hypothesized that D-glucosamine (D-GlcN) and Thiamet-G, two agents that increase protein O-GlcNAcylation via different mechanisms, inhibit TNF-alpha-induced oxidative stress and vascular dysfunction by suppressing inducible nitric oxide (NO) synthase (iNOS) expression. Rat aortic rings were incubated for 3h at 37 degrees C with D-GlcN or its osmotic control L-glucose (L-Glc) or with Thiamet-G or its vehicle control (H2O) followed by the addition of TNF-alpha or vehicle (H2O) for 21 h. After incubation, rings were mounted in a myograph to assess arterial reactivity. Twenty-four hours of incubation of aortic rings with TNF-alpha resulted in 1) a hypocontractility to 60 mM K+ solution and phenylephrine, 2) blunted endothelium-dependent relaxation responses to ACh and substance P, and 3) unaltered relaxing response to the Ca2+ ionophore A-23187 and the NO donor sodium nitroprusside compared with aortic rings cultured in the absence of TNF-alpha. D-GlcN and Thiamet-G pretreatment suppressed the TNF-alpha-induced hypocontractility and endothelial dysfunction. Total protein O-GlcNAc levels were significantly higher in aortic segments treated with D-GlcN or Thiamet-G compared with controls. Expression of iNOS protein was increased in TNF-alpha-treated rings, and this was attenuated by pretreatment with either D-GlcN or Thiamet-G. Dense immunostaining for nitrotyrosylated proteins was detected in the endothelium and media of the aortic wall, suggesting enhanced peroxynitrite production by iNOS. These findings demonstrate that acute increases in protein O-GlcNAcylation prevent TNF-alpha-induced vascular dysfunction, at least in part, via suppression of iNOS expression.

• 出版日期2012-9
• 单位扬州大学