Specific O-GlcNAc modification at Ser-615 modulates eNOS function.

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ID: 113454
2020
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Abstract
Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and devastating disease characterized by vascular smooth muscle and endothelial cell proliferation leading to a narrowing of the vessels in the lung. The increased resistance in the lung and the higher pressures generated result in right heart failure. Nitric Oxide (NO) deficiency is considered a hallmark of IPAH and altered function of endothelial nitric oxide synthase (eNOS), decreases NO production. We recently demonstrated that glucose dysregulation results in augmented protein serine/threonine hydroxyl-linked N-Acetyl-glucosamine (O-GlcNAc) modification in IPAH. In diabetes, dysregulated glucose metabolism has been shown to regulate eNOS function through inhibition of Ser-1177 phosphorylation. However, the link between O-GlcNAc and eNOS function remains unknown. Here we show that increased protein O-GlcNAc occurs on eNOS in PAH and Ser-615 appears to be a novel site of O-GlcNAc modification resulting in reduced eNOS dimerization. Functional characterization of Ser-615 demonstrated the importance of this residue on the regulation of eNOS activity through control of Ser-1177 phosphorylation. Here we demonstrate a previously unidentified regulatory mechanism of eNOS whereby the O-GlcNAc modification of Ser-615 results in reduced eNOS activity and endothelial dysfunction under conditions of glucose dysregulation.
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aulak2020specificredox Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Aulak, Kulwant S;Barnes, Jarrod W;Tian, Liping;Mellor, Noel E;Haque, Mohammad M;Willard, Belinda;Li, Ling;Comhair, Suzy C;Stuehr, Dennis J;Dweik, Raed A;
Journal Redox biology
Year 2020
DOI
S2213-2317(20)30830-2
URL
Keywords
nitric oxide pulmonary arterial hypertension endothelial nitric oxide synthetase o-glcnac modification

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