Jian Xu, PhD
Associate Professor of Medicine
Dr. Xu's Research Group
941 Stanton L. Young Blvd.,
Lab - BSEB 330
Oklahoma City, OK 73104
office ext 48495
lab ext 52604
Patients with diabetes are at significantly increased risk for both microvascular and cardiovascular adverse events. This is because diabetes promotes disease in nearly all blood vessel types and sizes. Vascular complications are responsible for most of the morbidity, hospitalizations, and mortality in patients with diabetes. Dysregulated endothelial function is one of the major factors contributing to the development of vascular complications in diabetes. By using cell culture and mouse models, our lab explores endothelial regulated pathways that lead to dysmetabolism, a characteristic of metabolic disorders, including diabetes, insulin resistance, and obesity. Our previous research investigated the roles of endothelial regulation on peripheral angiogenesis and dysregulated inflammation in diabetes. As a logical extension to these studies, our current research centers on mechanisms underlying the endothelial regulation of metabolic disorders. Our long-term goal is to translate our bench-side pre-clinical findings to the bedside clinical practice, by providing insights into the development of much-needed management and therapy for these disorders.
Mechanisms regulating peripheral angiogenesis in diabetes mellitus
In diabetes, impaired physiological angiogenesis delays wound healing, exacerbates peripheral limb ischemia, and can even cause cardiac mortality due to a lack of collateral vessel development. However, effective therapies to restore peripheral angiogenesis are elusive. It is unclear how diabetes regulates angiogenesis. We recently found that methylglyoxal (MGO), a metabolite elevated in patients with diabetes, impaired angiogenesis by reducing protein levels of vascular endothelial growth factor receptor 2 (VEGFR2). VEGFR2 is a key angiogenic protein that is downregulated in patients with diabetes and in diabetic mouse models. Our published data showed for the first time that VEGFR2 could be reduced by MGO-activated autophagy in cultured endothelial cells. Building on these data, we seek to understand the role and mechanism of autophagy in diabetic angiogenesis impairment, focusing on autophagy-mediated endothelial cell proliferation, matrix degradation, migration, tube formation, and vessel maturation affected by diabetes. Our goals will be achieved through experiments using genetic and pharmacological approaches in cell culture and mouse models of diabetes. With these approaches, we have identified endothelial autophagy-dependent and independent pathways regulating angiogenesis in diabetes.
Mechanisms modulating inflammatory response in diabetes mellitus
Inflammation is a characteristic of both type 1 and type 2 diabetes. Overwhelming evidence demonstrates the association of oxidative stress with vascular inflammatory response in hyperglycemia through mechanisms that are not fully elucidated. Protein degradation by the ubiquitin-proteasome system is central to cell homeostasis and survival. Defects in this process are associated with cancers and neurodegenerative disorders. However, the role of the ubiquitin-proteasome system in diabetes remains largely unknown. Using a proteasome reporter mouse model, we provided the first evidence that early hyperglycemia enhanced 26S proteasome functionality, contributing to elevated endothelial inflammatory response in diabetes. By monitoring 26S proteasome functionality in various mouse models of diabetes, we have identified new endogenous regulators (e.g., eNOS-derived nitric oxide), and new substrates (e.g., O-linked-GlcNAc transferase) that are relevant to vascular inflammation. Consequently, we have begun to understand the significance of protein homeostasis (proteostasis) in diabetes, which could provide insights into the development of therapeutic strategies for diabetes-associated dysregulated inflammation.
Mechanisms causing metabolic dysfunction in diabetes, obesity, and insulin resistance
An increasing body of evidence supports the evolving concept that functional interactions between organs/tissues are essential for metabolic homeostasis. Understanding the cause of metabolic dysfunction and diabetes will also require a detailed understanding of how these different tissues and organs work together. The endothelium forms the inner cellular lining of blood vessels by highly metabolically active endothelial cells. The endothelium has long been regarded as an integrated system, like an organ; however, the role and mechanism of endothelium in metabolic homeostasis has just emerged. Our previous studies of the endothelial regulation of cardiovascular complications in diabetes have set a stage on which we will be able to test the role and mechanism of endothelial cross-talk with metabolic organs and tissues. We expect to achieve these goals with genetic and pharmacological approaches in cell co-culture and mouse models of diabetes, obesity, and insulin resistance. Our pilot studies have revealed unexpectedly complex modes of endothelial interactions with metabolic organs/tissues, depending, at least in part, on duration of disease (e.g., diabetes and/or obesity) and locations of impacts (e.g., fat, liver, or skeletal muscle), which warrants further investigations of their clinical implication and translation.
||Postdoctoral Fellow, University of Oklahoma Health Sciences Center, OK
||Postdoctoral Fellow, University of Tennessee Medical Center, TN
||Postdoctoral Fellow, University of Konstanz, Konstanz, Germany
||PhD - Biochemical Pharmacology, University of Konstanz, Konstanz, Germany
||MS - Biochemistry, Xinjiang Agricultural University, Urumqi, China
||BS - Biology, Shaanxi Normal University, Xi'an, China
Li M, Qian M, Kyler K, Xu, J*. Endothelial–vascular smooth muscle cells interactions in atherosclerosis. Frontiers in Cardiovascular Medicine. 2018 Oct 23; 5:151. PMID: 30406116 PMCID: PMC6207093
Rao G, Nkepang G, Xu J, Yari H, Houson H, Awasthi V. Ubiquitin receptor RPN13 mediates the inhibitory interaction of diphenyldihaloketones CLEFMA and EF24 with the 26S proteasome. Frontiers in Chemistry (Chemical Biology). 2018: 6 (392), 1-13. PMID: 30280096.
Wu H, Rahman H, Dong Y, Liu X, Lee Y, Wen A, To K, Xiao L, Yang W, Birsner A, Bazinet L, Wong S, Song K, Brophy M, Mahamud M, Chang B, Cai X, Pasula S, Kwak S, Xu J, Bischoff J, Bielenberg D, Dixon, BJ, D’Amato JR, Srinivasan SR, Chen H. Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes. Journal of Clinical Investigation. 2018: 128(9), 4025-4043. PMID: 30102256.
Li M, Qian M, Xu J*. Vascular endothelial regulation of obesity-associated insulin resistance. Frontiers in Cardiovascular Medicine. 2017; Aug 9; 4:51. PMID: 28848738 PMCID: PMC5552760
Klionsky DJ, Abdelmohsen K, Abe A, Abeliovich H, Arozena AA, Adler SG, Xu J, Ziparo E, Zois CE, Zoladek T, Zong WX, Zorzano A, Zughaier SM. Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy (3rd edition). Autophagy. 2016; 12(1) 1-222. PMID: 26799652
Xing J, Liu H, Yang H, Chen R, Chen Y, Xu J*. Upregulation of Unc-51-like kinase 1 by nitric oxide stabilizes SIRT1, independent of autophagy.PLoS One 2014, 9(12):e116165. PMID: 25541949. PMCID: PMC4277463
Liu H, Wang Z, Yu S, Xu J*. Proteasomal degradation of O-GlcNAc transferase elevates hypoxia-induced vascular endothelial inflammatory response.Cardiovascular Research2014, 103(1):131-139. PMID: 24788415. PMCID: PMC4133591
Liu H, Wang Z, Yu S and Xu J*. (2014). Proteasomal degradation of O-GlcNAc transferase elevates hypoxia-induced vascular endothelial inflammatory response.Cardiovascular Research2014. Apr 29. [Epub ahead of print] PMID: 24788415 (Accepted).
Liu H, Yu S, Zhang H and Xu J*. (2014). Identification of nitric oxide as an endogenous inhibitor of 26S proteasomes in vascular endothelial cells.PLoS ONE (Accepted).
Li Y, Liu H, Xu QS, Du YG and Xu J*. (2014). Chitosan oligosaccharides block LPS-induced O-GlcNAcylation of NF-κB and endothelial inflammatory response. Carbohydr Polym.2014; 99:568-78. PMCID: PMC3843148
Liu H, Yu S, Zhang H and Xu J*.(2012). Angiogenesis impairment in diabetes: Role of methylglyoxal-induced receptor for advanced glycation endproducts, autophagy and vascular endothelial growth factor receptor 2.PLoS ONE.7(10):e46720. PMID: 23056421. PMCID: PMC3463541
Liu H, Yu S, Xu W and Xu J*. (2012). Enhancement of 26S proteasome functionality connects oxidative stress and vascular endothelial inflammatory response in diabetes.Arteriosclerosis, Thrombosis, and Vascular Biology.32 (9):2131-2140. PMID: 22772755.
Xu J, Wang SX, Viollet B and Zou MH. (2012). Regulation of the proteasome by AMPK in endothelial cells: the role of O-GlcNAc transferase (OGT).PLoS One.2012;7(5):e36717.
Xu J*, Wang SX, Zhang M, Wang QL, Asfa S and Zou MH. (2012). PA700 nitration links proteasome activation to endothelial dysfunction in mouse models of cardiovascular risk factors.PLoS One.2012;7(1):e29649.
Zhang M, Song P, Xu J, and Zou MH. (2011). Activation of NAD(P)H oxidases by thromboxane A2 receptor uncouples endothelial nitric oxide synthase.Arteriosclerosis, Thrombosis, and Vascular Biology.31(1):125-132.
Wang S, Zhang M, Liang B, Xu J, Xie Z, Liu C, Viollet B, Yan D, and Zou MH. (2010). AMPKalpha2 causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: role of 26S proteasomes.Circulation Research.106(6):1117-28.
Xu J, and Zou MH. (2009).Molecular Insights and Therapeutic Targets for Diabetic Endothelial Dysfunction.Circulation.120(13):1266-86.
Xu J, Wang S, Wu Y, Song P, andZou MH. (2009).Tyrosine nitration of PA700 activates 26S proteasomes to induce endothelial functions in angiotensin II-induced hypertension.Hypertension.54:625-632.
Wang S, Zhang M, Xu J, Song P, andZou MH. (2009).In VivoActivation of AMP-activated Protein Kinase Attenuates Diabetes-enhanced Degradation of GTP Cyclohydrolase I.Diabetes.58(8):1893-901.
Song P, Zhang M, Wang S, Xu J, Choi HC, and Zou MH. (2009). Thromboxane A2 receptor activates a Rho-associated kinase/LKB1/PTEN pathway to attenuate endothelium insulin signaling.J Biol Chem, 284:17120-17128.
Wang SX, Xu J, Song P, Wu Y, and Zou MH. (2008). Acute Inhibition of GTP Cyclohydrolase 1 Uncouples Endothelial Nitric Oxide Synthase and Elevates Systolic Blood Pressure.Hypertension. 52(3):484-90.
Dong Y, Wu Y, Wu M, Wang S, Zhang J, Xie Z, Xu J, Song P, Wilson K, Zhao Z, Lyons T, and Zou MH. (2008). Activation of Protease Calpain by Oxidized and Glycated LDL Increases the Degradation of Endothelial Nitric Oxide Synthase.J Cell Mol Med. Jun 28. [Epub ahead of print]
Choi HC, Song P, Xie Z, Wu Y, Xu J, Zhang M, Dong Y, Wang S, Lau K, and Zou MH. (2008). Reactive Nitrogen Species Is Required for the Activation of the AMP-activated Protein Kinase by Statin in Vivo.J Biol Chem.Jul 18;283(29):20186-97.
Song P, Xie Z, Wu Y, Xu J, Dong Y, and Zou MH. (2008). Protein kinase C zeta -dependent LKB1 serine 428 phosphorylation increases LKB1 nucleus export and apoptosis in endothelial cells.J Biol Chem. 283(18):12446-55.
Zhang M, Dong Y, Xu J, Xie Z, Wu Y, Song P, Guzman M, and Zou MH. (2008). Thromboxane receptor via hydrogen peroxide activates the AMP-activated kinase in vascular smooth muscle cells.Circulation Research102(3):328-37.
Wenzel P, Daiber A, Oelze M, Brandt M, Closs E, Xu J, Thum T, Bauersachs J, Ertl G, Zou MH, Förstermann U, and Münzel T. (2008). Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus.Atherosclerosis. 198(1):65-76.
Song P, Wu Y, Xu J, Xie Z, Dong Y, Zhang M, and Zou MH. (2007) Reactive nitrogen species induced by hyperglycemia suppresses Akt signaling and triggers apoptosis by upregulating phosphatase PTEN in an LKB1-dependent manner.Circulation. 116 (14): 1585-95.
Xu J, Wu Y, Song P, Zhang M, Wang SX, and Zou MH. (2007). Proteasome-dependent degradation of guanosine 5-triphosphate cyclohydrolase I causes tetrahydrobiopterin deficiency in diabetes mellitus.Circulation. 116 (8): 944-53.
Wu Y, Song P, Xu J, Zhang M, and Zou MH. (2007). Activation of protein phosphoatase PP2A by palmitic acid inhibits the AMP-activated protein kinase (AMPK).Journal of Biological Chemistry. 30; 282(13):9777-9788.
Xu J, Xie Z, Reece R, David Pimental, and Ming-Hui Zou. (2006). Uncoupling of endothelial nitric oxide synthase by Hypochlorous acid. Role of vascular NAD(P)H oxidase-derived superoxide and peroxynitrite.Arteriosclerosis, Thrombosis, and Vascular Biology.26(12):2688-2695.
*Comment in (Editorial): Rabelink TJ and von Zonneveld AJ: Coupling eNOS uncoupling to the innate immune response.Arteriosclerosis, Thrombosis, and Vascular Biology.26(12):2585-2587, 2006.
Nie H, Wu JL, Zhang M, Xu J and Zou MH. (2006). Endothelial nitric oxide synthase-dependent tyrosine nitration of prostacyclin synthase in diabetes mellitus in vivo.Diabetes.55(11):3133-3141.
Xing JH, Liu HT, Yang HB, Li M, and Xu J*.(2015). A New Mediator of SIRT1 Protein Turnover Regulated by Endothelial Nitric Oxide. American Diabetes Association's 75th Scientific Sessions, June 5−9, 2015, Boston, MA (this abstract has also been selected to be showcased in aGuided Audio Poster
Liu HT, Xing JH, Yu SJ, and Xu J*.(2014). LC3B-mediated Degradation of the Vascular Endothelial Growth Factor Receptor 2 Impaired Angiogenesis in Diabetes. American Diabetes Association's 74th Scientific Sessions, June 13−17, 2014, San Francisco, CA (Oral Presentation)
Liu HT, Xing JH, Li Y and Xu J*.(2013). Proteasomal Degradation of O-GlcNAc Transferase Enhances Hypoxia-Mediated Vascular Endothelial Inflammatory Response. American Heart Association's 2013 Scientific Sessions, November 16−20, Dallas, TA
Liu HT, Yu SJ, Li Y and Xu J*.(2013). The Endothelial Nitric Oxide Synthase Derived Nitric Oxide Regulates Vascular 26S Proteasome Functionality. American Diabetes Association's 73rd Scientific Sessions, June 21-25, 2013 in Chicago, IL
Xu J, Pantalia M, Lau A, Eby B, Skaggs C, Yu SJ, Liu HT, Ma JX and Lau K (2011). Diabetic Nephropathy (DN) in Insulin-Deficient Mouse Models: Longitudinal Functional & Ultrasonic Documentation of Progressive Decline in Glomerular Filtration Rate (GFR) & the Role of Reduced Oxidative/Nitrosative Stress in Metformin Renoprotection. The American Society of Nephrology 2011 Meetings Philadelphia, PA
Eby B, Atkins RM, Skaggs C, Xu J, Ong E, Abramowitz J, Tsiokas L, Birnbaumer L and Lau K (2011). Metabolic Syndrome due to Deletion of the Gene Encoding Canonical Transient Receptor Potential Channel 1 (TRPC1): A Novel Model Induced by Hyperphagia & Associated with Key Organ Dysfunctions. The American Society of Nephrology 2011 Meetings Philadelphia, PA
Liu HT, Yu SJ, and Xu J.(2011). Hyperglycemia induced 26S proteasome activation is an early event in streptozotocin−treated mice. American Diabetes Association's 71st Scientific Sessions, June 24−28, 2011, San Diego, California (this abstract has also been selected to be showcased in aGuided Audio Poster Tour).
Liu HT, Yu SJ, and Xu J.*(2011). Hyperglycemia activates 26S proteasome in STZ-treated mice. Central RegionIDEAConference. Omaha, NE, May 23-25, 2011. (*Corresponding author and selected as an oral presentation).