Regulatory Effects of O-GlcNAcylation in Vascular Smooth Muscle Cells on Diabetic Vasculopathy

Abstract

Vascular complications from uncontrolled hyperglycemia are the leading cause of death in patients with diabetes mellitus. Previous reports have shown a strong correlation between hyperglycemia and vascular calcification, which increases mortality and morbidity in individuals with diabetes. However, the precise underlying molecular mechanisms of hyperglycemia-induced vascular calcification remain largely unknown. Transdifferentiation of vascular smooth muscle cells (VSMC) into osteoblast-like cells is a known culprit underlying the development of vascular calcification in the diabetic vasculature. Pathological conditions such as high glucose levels and oxidative stress are linked to enhanced osteogenic differentiation of VSMC both in vivo and in vitro . It has been demonstrated that increased expression of runt-related transcription factor 2 (Runx2), a bone-related transcription factor, in VSMC is necessary and sufficient for the induction of VSMC calcification. Addition of a single O-linked β-N-acetylglucosamine (O-GlcNAc) moiety to the serine/threonine residues of target proteins (O-GlcNAcylation) has been observed in the arteries of diabetic patients, as well as in animal models in association with the enhanced expression of Runx2 and aggravated vascular calcification. O-GlcNAcylation is a dynamic and tightly regulated process, that is mediated by 2 enzymes, O-GlcNAc transferase and O-GlcNAcase. Glucose is metabolized into UDP-β-D-N-acetylglucosamine, an active sugar donor of O-GlcNAcylation via the hexosamine biosynthetic pathway. Overall increases in the O-GlcNAcylation of cellular proteins have been closely associated with cardiovascular complications of diabetes. In this review, the authors provide molecular insights into cardiovascular complications, including diabetic vasculopathy, that feature increased O-GlcNAcylation in people with diabetes.

Positive Association of Leptin and Artery Calcification of Lower Extremity in Patients With Type 2 Diabetes Mellitus: A Pilot Study

“…Previous studies showed VC is the main independent risk factor for morbidity and mortality of cardiovascular diseases with diabetes ( 29 , 30 ). Hyperglycemia and increased glycation end products, hyperinsulinemia, oxidative stress, lipid metabolism disturbance, inflammation, apoptosis and abnormal expression of bone regulatory protein are the main factors of vascular calcification in T2DM, which are closely related to the occurrence and development of vascular calcification ( 31 , 32 ). In a population-based multi-ethnic cohort ( 33 ), Katz et al.…”

Glycation and Glycosylation in Cardiovascular Remodeling: Focus on Advanced Glycation End Products and O-Linked Glycosylations as Glucose-Related Pathogenetic Factors and Disease Markers

“…O-GlcNAcylation promotes osteoblastic differentiation with enhanced expression of bonerelated markers such as alkaline phosphatase, osteocalcin, and bone sialoprotein via transcriptional activation of runt-related transcription factor 2 (Runx2), an osteogenic transcription factor. O-GlcNAcylation of Runx2 stimulated mineralization of extracellular matrix [188]. Furthermore, increased O-GlcNAcylation levels reduce endothelium-dependent relaxation through the overproduction of ROS via activation of NADPH oxidase [189].…”

O-Linked β-N-Acetylglucosamine Modification: Linking Hypertension and the Immune System

“…In this sense, there is direct evidence that elevated levels of protein O-GlcNAcylation in endothelial cells impairs endothelium-dependent relaxation ( 44 , 47 – 49 ), demonstrating that O-GlcNAcylation leads to endothelial dysfunction. Furthermore, O-GlcNAcylation of vascular smooth muscle cells augments vascular response to contractile agonists ( 50 , 51 ) and favors vascular calcification ( 52 – 54 ), resulting in high blood pressure ( 25 ).…”