Vascular calcification is prevalent in patients with diabetes mellitus, which increases their morbidity and mortality. Hyperglycemia is a hallmark of diabetes that leads to adverse vascular complications. Emerging clinical and basic investigations support a strong correlation between hyperglycemia and vascular calcification. However, the precise role of hyperglycemia in regulating vascular calcification and the underlying molecular mechanisms remain unknown. Osteogenic differentiation and calcification of vascular smooth muscle cells (VSMC) directs vascular calcification in the media and intima of diabetic vasculature. Conditions associated with diabetes, including high glucose and oxidative stress, have been reported to induce VSMC calcification in culture. We have found that oxidative stress and high glucose increase the expression of the osteogenic transcription factor Runx2, which is essential and sufficient to induce VSMC calcification in vitro and in vivo. Increased protein modification by O-linked ss-N-acetyl-glucosamine (O-GlcNAcylation) was observed in diabetic arteries from human and mice, which was associated with increased Runx2 and vascular calcification. O- GlcNAcylation is a dynamic and tightly regulated process, which is as common and ubiquitous as phosphorylation and plays a key role in the regulation of diverse biological processes. O-GlcNAcylation is catalyzed by two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which catalyze the transfer and removal of O-GlcNAc on target proteins, respectively. Glucose metabolized via the hexosamine biosynthesis pathway increases the production of UDP-GlcNAc, an active sugar donor for O-GlcNAcylation, which elevates O-GlcNAcylation. Increased O-GlcNAcylation has been associated with the adverse cardiovascular effects of diabetes. Our preliminary results demonstrated that high glucose and oxidative stress increased VSMC O-GlcNAcylation and calcification. Elevation of O-GlcNAcylation via OGA knockdown promoted VSMC calcification. Moreover, deletion of OGT not only decreased high glucose and oxidative stress-induced protein O-GlcNAcylation in VSMC, but also blocked VSMC calcification. Therefore, we hypothesize that inhibition of O-GlcNAcylation by OGT deletion in VSMC decreases vascular calcification in diabetes. Using our newly generated inducible SMC-specific OGT knockout mouse model, we will 1) determine the role of OGT-mediated O-GlcNAcylation in diabetic vascular calcification in vivo;and 2) elucidate O-GlcNAcylation-dependent molecular signals that regulate vascular calcification. These studies will provide important molecular insights into developing new strategies or drugs to prevent or treat vascular calcification in diabetes and other vascular diseases featuring increased O-GlcNAcylation.
This proposal will focus on elucidating novel molecular mechanisms underlying O-GlcNAcylation-regulated vascular smooth muscle cell phenotype and osteogenic differentiation that contribute to diabetic vasculopathy. We have demonstrated that increased O-GlcNAcylation was associated with vascular calcification in diabetic arteries from human and mice;and a direct effect of O-GlcNAcylation in regulating smooth muscle cell calcification in vitro;the proposed studies will determine a definitive role of O-GlcNAcylation-regulated molecular signals in regulating vascular calcification in diabetes with tissue-specific knockout mice. Our studies will provide important molecular insights into the function of O-GlcNAcylation in regulating diabetic vasculopathy, which will lead to the development of novel strategy or drugs for prevention and therapy of these diabetic complications.
|Su, Hairui; Sun, Chiao-Wang; Liu, Szu-Mam et al. (2018) Defining the epigenetic status of blood cells using a cyanine-based fluorescent probe for PRMT1. Blood Adv 2:2829-2836|
|Yang, Youfeng; Sun, Yong; Chen, Jianye et al. (2018) AKT-independent activation of p38 MAP kinase promotes vascular calcification. Redox Biol 16:97-103|
|Sun, Yong; Byon, Chang Hyun; Yang, Youfeng et al. (2017) Dietary potassium regulates vascular calcification and arterial stiffness. JCI Insight 2:|
|Byon, Chang Hyun; Heath, Jack M; Chen, Yabing (2016) Redox signaling in cardiovascular pathophysiology: A focus on hydrogen peroxide and vascular smooth muscle cells. Redox Biol 9:244-253|
|Tran, Ngoc-Tung; Su, Hairui; Khodadadi-Jamayran, Alireza et al. (2016) The AS-RBM15 lncRNA enhances RBM15 protein translation during megakaryocyte differentiation. EMBO Rep 17:887-900|
|Ma, Liping; Ambalavanan, Namasivayam; Liu, Hui et al. (2016) TLR4 regulates pulmonary vascular homeostasis and remodeling via redox signaling. Front Biosci (Landmark Ed) 21:397-409|
|Byon, Chang Hyun; Chen, Yabing (2015) Molecular Mechanisms of Vascular Calcification in Chronic Kidney Disease: The Link between Bone and the Vasculature. Curr Osteoporos Rep 13:206-15|
|Deng, Liang; Huang, Lu; Sun, Yong et al. (2015) Inhibition of FOXO1/3 promotes vascular calcification. Arterioscler Thromb Vasc Biol 35:175-83|
|Heath, Jack M; Sun, Yong; Yuan, Kaiyu et al. (2014) Activation of AKT by O-linked N-acetylglucosamine induces vascular calcification in diabetes mellitus. Circ Res 114:1094-102|