Jian Xu, PhD
Assistant 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
Mechanisms of diabetic impairment of angiogenesis
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 angiogenesis are elusive. It is unclear how diabetes impairs 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 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.
Mechanisms of sustained inflammation in diabetes
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, our laboratory provided the first evidence that early hyperglycemia enhanced 26S proteasome functionality, which elevated the NF-κB-mediated endothelial inflammatory response in diabetes. By monitoring 26S proteasome functionality under chronic hyperglycemia in mouse models of diabetes, we have identified new endogenous regulators and new substrates that are relevant to vascular homeostasis and sustained inflammation. Consequently, we have begun to understand the significance of 26S proteasomes in diabetes. If successful, the results of these studies will provide insights into the development of therapeutic strategies for diabetes and its vascular complications.
||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
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).