Chang Hyun Byon

Chonnam National University

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Yabing Chen

University of Alabama at Birmingham

Jack Heath

St. Vincent's Birmingham

Jay M. McDonald

University of Alabama at Birmingham

Xia Mao

Nantong University

Yong Sun

Nanjing Medical University

Soo Wan Kim

Chonnam National University Hospital

Simon T. Hui

University of California, Los Angeles

Danny R. Welch

The University of Kansas Cancer Center

Nirag Jhala

Rutgers, The State University of New Jersey

Seong Kwon

Chonnam National University

Cooperative Institutions

University of Alabama at Birmingham

Birmingham VA Medical Center

University of California, Los Angeles

Chonnam National University

University of Alabama

Chonnam National University Hospital

Sun Yat-sen University

Huazhong University of Science and Technology

St. Vincent's Birmingham

Saint Louis University

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Oxidative Stress Induces Vascular Calcification through Modulation of the Osteogenic Transcription Factor Runx2 by AKT Signaling

Journal of Biological Chemistry (2008)

Chang Hyun Byon Amjad Javed Qun Dai John C. Kappes Thomas L. Clemens

Oxidative stress plays a critical role in the pathogenesis of atherosclerosis including the formation of lipid laden macrophages and the development of inflammation. However, oxidative stress-induced molecular signaling that regulates the development of vascular calcification has not been investigated in depth. Osteogenic differentiation of vascular smooth muscle cells (VSMC) is critical in the development of calcification in atherosclerotic lesions. An important contributor to oxidative stress in atherosclerotic lesions is the formation of hydrogen peroxide from diverse sources in vascular cells. In this study we defined molecular signaling that is operative in the H2O2-induced VSMC calcification. We found that H2O2 promotes a phenotypic switch of VSMC from contractile to osteogenic phenotype. This response was associated with an increased expression and transactivity of Runx2, a key transcription factor for osteogenic differentiation. The essential role of Runx2 in oxidative stress-induced VSMC calcification was further confirmed by Runx2 depletion and overexpression. Inhibition of Runx2 using short hairpin RNA blocked VSMC calcification, and adenovirus-mediated overexpression of Runx2 alone induced VSMC calcification. Inhibition of H2O2-activated AKT signaling blocked VSMC calcification and Runx2 induction concurrently. This blockage did not cause VSMC apoptosis. Taken together, our data demonstrate a critical role for AKT-mediated induction of Runx2 in oxidative stress-induced VSMC calcification.

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10.1074/jbc.m800021200

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Renoprotective Effects of Maslinic Acid on Experimental Renal Fibrosis in Unilateral Ureteral Obstruction Model via Targeting MyD88

Frontiers in Pharmacology (2021)

Wenjuan Sun Chang Hyun Byon Dong Hyun Kim Hoon Choi Jung Sun Park

Maslinic acid (MA), also named crategolic acid, is a pentacyclic triterpene extracted from fruits and vegetables. Although various beneficial pharmacological effects of MA have been revealed, its effect on renal fibrosis remains unclear. This study was designed to clarify whether MA could attenuate renal fibrosis and determine the putative underlying molecular mechanisms. We demonstrated that MA-treated mice with unilateral ureteral obstruction (UUO) developed a histological injury of low severity and exhibited downregulated expression of fibrotic markers, including α-smooth muscle actin (α-SMA), vimentin, and fibronectin by 38, 44 and 40%, and upregulated expression of E-cadherin by 70% as compared with untreated UUO mice. Moreover, MA treatment restored the expression levels of α-SMA, connective tissue growth factor, and vimentin to 10, 7.8 and 38% of those induced by transforming growth factor (TGF)-β in NRK49F cells. MA decreased expression of Smad2/3 phosphorylation and Smad4 in UUO kidneys and TGF-β treated NRK49F cells (

10.3389/fphar.2021.708575

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

Journal of Lipid and Atherosclerosis (2020)

Chang Hyun Byon Soo Wan Kim

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.

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10.12997/jla.2020.9.2.243

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Redox signaling in cardiovascular pathophysiology: A focus on hydrogen peroxide and vascular smooth muscle cells

Redox Biology (2016)

Chang Hyun Byon Jack Heath Yabing Chen

Oxidative stress represents excessive intracellular levels of reactive oxygen species (ROS), which plays a major role in the pathogenesis of cardiovascular disease. Besides having a critical impact on the development and progression of vascular pathologies including atherosclerosis and diabetic vasculopathy, oxidative stress also regulates physiological signaling processes. As a cell permeable ROS generated by cellular metabolism involved in intracellular signaling, hydrogen peroxide (H2O2) exerts tremendous impact on cardiovascular pathophysiology. Under pathological conditions, increased oxidase activities and/or impaired antioxidant systems results in uncontrolled production of ROS. In a pro-oxidant environment, vascular smooth muscle cells (VSMC) undergo phenotypic changes which can lead to the development of vascular dysfunction such as vascular inflammation and calcification. Investigations are ongoing to elucidate the mechanisms for cardiovascular disorders induced by oxidative stress. This review mainly focuses on the role of H2O2 in regulating physiological and pathological signals in VSMC.

Pathogenesis

Cell Signaling

Pathophysiology

10.1016/j.redox.2016.08.015

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Citations (143)

Molecular Mechanisms of Vascular Calcification in Chronic Kidney Disease: The Link between Bone and the Vasculature

Current Osteoporosis Reports (2015)

Chang Hyun Byon Yabing Chen

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Bone remodeling

10.1007/s11914-015-0270-3

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Abstract 917: AKT-Runx2 Signaling Regulates Oxidative Stress-induced Vascular Smooth Muscle Cell Calcification

Circulation (2007)

Chang Hyun Byon McDonald M Jay Yabing Chen

Oxidative stress plays a critical role in the pathogenesis of atherosclerosis, including the development of atherovascular calcification, a prominent feature of atherosclerosis. Enhanced osteogenic...

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β-Elemene Attenuates Renal Fibrosis in the Unilateral Ureteral Obstruction Model by Inhibition of STAT3 and Smad3 Signaling via Suppressing MyD88 Expression

International Journal of Molecular Sciences (2022)

Wenjuan Sun Dong-Hyun Kim Chang Hyun Byon Hoon Choi Jung Sun Park

Renal fibrosis is a chronic pathological process that seriously endangers human health. However, the current therapeutic options for this disease are extremely limited. Previous studies have shown that signaling factors such as JAK2/STAT3, Smad3, and Myd88 play a regulatory role in renal fibrosis, and β-elemene is a plant-derived sesquiterpenoid organic compound that has been shown to have anti-inflammatory, anti-cancer, and immunomodulatory effects. In the present study, the anti-fibrotic effect of β-elemene was demonstrated by in vivo and in vitro experiments. It was shown that β-elemene inhibited the synthesis of extracellular matrix-related proteins in unilateral ureteral obstruction mice, and TGF-β stimulated rat interstitial fibroblast cells, including α-smooth muscle actin, vimentin, and connective tissue growth factor, etc. Further experiments showed that β-elemene reduced the expression levels of the above-mentioned fibrosis-related proteins by blocking the phosphorylation of JAK2/STAT3, Smad3, and the expression or up-regulation of MyD88. Notably, knockdown of MyD88 attenuated the phosphorylation levels of STAT3 and Smad3 in TGF-β stimulated NRK49F cell, which may be a novel molecular mechanism by which β-elemene affects renal interstitial fibrosis. In conclusion, this study elucidated the anti-interstitial fibrosis effect of β-elemene, which provides a new direction for future research and development of drugs related to chronic kidney disease.

10.3390/ijms23105553

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Citations (9)

Free fatty acids enhance breast cancer cell migration through plasminogen activator inhibitor-1 and SMAD4

Laboratory Investigation (2009)

Chang Hyun Byon Robert W. Hardy Changchun Ren Selvarangan Ponnazhagan Danny R. Welch

Plasminogen activator inhibitor-1

10.1038/labinvest.2009.97

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Citations (49)

Abstract 2093: Protein O-GlcNAcylation is Important for Vascular Calcification in Diabetes

Journal of Biological Chemistry (2023)

Yong Sun Chang Hyun Byon Yong Sun Jack Heath Xia Mao

10.1016/j.jbc.2023.103899

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Abstract 15322: O-glcnac Modification on Runx2 Promotes Vascular Calcification

Circulation (2022)

Chang Hyun Byon Yong Sun Jack Heath Xia Mao Xinyang Zhao

Vascular calcification is prevalent in patients with diabetes mellitus and well documented in animal models of diabetes. We have previously reported that vascular calcification in diabetes is associated with elevated vascular protein O -linked GlcNAc modification ( O -GlcNAcylation). The present studies sought to determine a causative link of O -GlcNAcylation with diabetic vascular calcification and the underlying molecular mechanisms. Using coronary arteries from diabetic subjects, we identified increased O -GlcNAcylation in the highly calcified lesions compared to those in the surrounding uncalcified areas. By generating a new mouse model with inducible SMC-specific deletion of the O -GlcNAc transferase (OGT), we demonstrated that smooth muscle cell (SMC)-specific OGT deletion significantly inhibited protein O -GlcNAcylation and calcification, and decreased aortic stiffness in the low-dose streptozotocin-induced diabetic mice. Consistent with the observations in human tissues, inhibition of vascular calcification by OGT ablation was associated with down-regulation of Runx2, the essential osteogenic regulator for vascular calcification. OGT deficiency in VSMC further attenuated Runx2-induced VSMC calcification. Immunoprecipitation analysis uncovered a direct O-GlcNAc modification on Runx2, which was abolished in the OGT-deficient VSMC. With a serial of Runx2 truncation mutants and point mutations on putative O -GlcNAcylation sites, we localized the essential Runx2 osteogenic functional domain between amino acids 391 and 432, and identified Runx2 T412 was responsible for Runx2 O -GlcNAcylation and Runx2-induced VSMC calcification. Inhibition of Runx2 O -GlcNAcylation by T412A mutation decreased Runx2 transcription activity and inhibited Runx2 binding with its key co-factors. Taken together, our studies have provided the first genetic proof demonstrating the causative effects of O -GlcNAcylation on vascular calcification in diabetes, and identified a novel mechanism underlying the essential role of O -GlcNAcylation of Runx2 in Runx2 osteogenic activity and Runx2-induced VSMC calcification. These results may shed lights on novel targets that are amenable to drug discovery for diabetic vascular calcification.

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10.1161/circ.146.suppl_1.15322

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