Jian Xu, PhD
Dr. Xu's Research Group
941 Stanton L. Young Blvd.,
Lab - BSEB 330
Oklahoma City, OK 73104
office ext 48495
lab ext 52604
The roles and mechanisms of regulated proteolysis in diabetic vascular complications
The ubiquitin-proteasome system is a major route for regulated protein degradation in eukaryotic cells. Deregulation of this system has been implicated in certain cancers, neurodegenerative disorders, and several cardiovascular diseases. However, the role of the proteasome in the pathogenesis of cardiovascular diseases remains largely unknown. We are the first to demonstrate alterations of 26S proteasome functionality in diabetes in vivo with a proteasome reporter mouse model. Emerging evidence also implicate that dysregulation of lysosomal autophagy, another major proteolytic system, plays a role in the pathogenesis of diabetic complications. The central goals of ongoing studies in our laboratory are to understand how diabetes alters the major proteolytic systems, what physiological and pathological significances of the alterations are, how these systems crosstalk in diabetes, and whether modulation of the systems specifically through a mechanism-dependent approach would ameliorate diabetic complications.
Therapeutic potential of natural products in cardiovascular disease
The incidence of diabetes-related blindness, amputations, heart attacks, and kidney failure continues to rise, indicating the limits to the expectation that current treatment modalities deliver. We are interested in natural products-associated alternatives, which have gained increased attention in the last decade. Our goal is to uncover the therapeutic potential of natural products in diabetes, particularly its cardiovascular complications. Our ongoing project exploits the inflammation-modulating potential of unrelated natural products or naturally occurring factors through biomarker-guided screening.
Currently our laboratory is funded to elucidate the mechanism of how oxidative post-translational modifications affect 26S proteasome functionality in the onset of endothelial dysfunction in diabetes and how the AMP protein kinase protects vascular function through the protein degradative machinery. The National Institutes of Health (CoBRE/PJI), the American Diabetes Association (ADA), the American Heart Association (AHA), and the Oklahoma Center for the Advancement of Science and Technology (OCAST) support these studies. These projects involve mouse models of diabetes, hypertension, and atherosclerosis, in combination with genetic and pharmaceutical approaches, both in cultured cells/tissues and transgenic mice.
||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
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. (Accepted).
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, and Zou 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, and Zou MH. (2009). In Vivo Activation 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 Research 102(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.
Liu HT, Yu SJ, and Xu J. (2012). Autophagy-mediated Reduction of Vascular Endothelial Growth Factor Receptor 2 Impairs Diabetic Angiogenesis. American Diabetes Association's 72nd Scientific Sessions, June 8−12, 2012, Philadelphia, Pennsylvania.
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 a Guided Audio Poster Tour).
Liu HT, Yu SJ, and Xu J.* (2011). Hyperglycemia activates 26S proteasome in STZ-treated mice. Central Region IDEA Conference. Omaha, NE, May 23-25, 2011. (*Corresponding author and selected as an oral presentation).
Xu J, Wang S, Zhang M, and Zou MH. (2010). 26S Proteasome is Implicated in Endothelial Dysfunction of Multiple Models with Cardiovascular Risk factors. ATVB 2010 Scientific Sessions, San Francisco, CA: April 8-10.
Xu J, Wang S, Wu Y, Song P, and Zou MH. (2009). Tyrosine Nitration of PA700 Activates 26S Proteasome to Induce Endothelial Dysfunction in Angiotensin II-infused Hypertensive
Mice. 69th Scientific Sessions of ADA, New Orleans, LA: June 5-9.
Xu J and Zou MH. (2008). Tyrosine nitration of PA700 activates the 26S proteasome to induce endothelial dysfunction in mice with angiotensin II-induced hypertension. The 3rd OPTM: Oxidative Post-Translational Modifications in the Cardiovascular System. Boston, MA. October 1-3.
Xu J, Wang SX, Wu Y, Song P, and Zou MH. (2007). Oxidative Stress Induces Endothelial Dysfunction: Role Ubiquitin-Proteasome System. 2007 Scientific Sessions of AHA, Orlando, Florida: November 4-7.
Xu J and Zou MH. (2006). Hyperglycemia-induced endothelial dysfunction is mediated by the proteasome-dependent degradation of GTP-cyclohydrolase I. Diabetes. 66th Scientific Sessions of ADA, Volume 55 Supplement 1, June, Cellular Mechanism in CVD (Cardio-Vascular Diseases): 139-OR, A33 (Oral presentation).
Xu J, Xie Z, Reece R, and Zou MH. (2005). Hypochlorite activates vascular NAD(P)H oxidase and uncouples endothelial nitric oxide synthase: Role of reactive nitrogen species. Circulation. 2005 Scientific Sessions of AHA, Volume 112, Number 17, October 25; Endothelial roles in atherosclerosis. II-141-142 (Oral presentation).
Xu J, Xie Z, Nelson J, Kirkpatrick S, and Zou MH. (2005). Hypochlorite-induced vascular endothelial dysfunction. The 6th Annual Conference on Arterosclerosis, Thrombosis, and Vascular Biology, the Grand Hyatt Washington, Washington, DC, April 28-30.