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

Redox Biology

Noel E. Mellor¹  Dennis J. Stuehr¹  Mohammad M. Haque¹  Kulwant S. Aulak¹  Liping Tian¹  Suzy C. Comhair¹  Jarrod W. Barnes¹  Raed A. Dweik¹  Ling Li²  Belinda Willard² 

[1] Inflammation and Immunity, Lerner Research Institute. Cleveland Clinic, OH, USA;Mass Spectrometry Laboratory for Protein Sequencing, Cleveland Clinic, OH, USA;

关键词: Endothelial nitric oxide synthetase;    O-GlcNAc modification;    Pulmonary arterial hypertension;    Nitric oxide;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown