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
Mechanisms of impaired angiogenesis in diabetes mellitus
Impaired physiological angiogenesis in diabetes causes delayed wound healing, exacerbated peripheral limb ischemia, and even cardiac mortality due to lack of collateral vessel development. However, effective therapies aiming at angiogenic restoration are elusive because it remains unclear how diabetes impairs the angiogenesis. Multiple mechanisms have been proposed. Reactive oxygen species have been implicated in the pathogenesis of major diabetic complications; although being regarded as independent risk factors for cardiovascular disease, the failure to demonstrate clinical benefit necessitates further studies to determine their role. Endothelial derangements and loss of endothelium-derived nitric oxide bioactivity have been shown to be important, yet the causal effect needs to be confirmed. Micro RNA alterations have been recently identified to contribute to delayed angiogenesis, although mechanism of the micro RNA regulation is unknown. Inhibition of protein kinase B by post-translational modification has been shown to lower angiogenesis, pending serum presence where the essential factor, if any, has yet to be identified. Growth factor deficiency has long been thought as the underlying mechanism; however, growth factors therapy in wound healing generates modest efficacy, indicating impaired growth factor signaling and the involvement of other essential angiogenic factors. Indeed, we were among the first to connect the impaired angiogenesis in diabetes to the reduction of the vascular endothelial growth factor receptor 2 that involved autophagy through the action of methylglyoxal. A reactive carbonyl species and a major precursor of advanced glycation end-products, methylglyoxal has been implicated in the pathophysiology of diabetes. Given the clear agreement of our findings with the clinical observations, we are seeking to understand the role of methylglyoxal in diabetic angiogenesis impairment, focusing on endothelial cell proliferation, matrix degradation, migration, tube formation, and vessel maturation. These aims will be achieved through experiments with both genetic and pharmacological approaches in cell culture and mouse models of diabetes.
The role of 26S proteasome functionality in diabetic vascular inflammation and endothelial homeostasis
Inflammation is a characteristic of both type 1 and type 2 diabetes. Overwhelming evidence implicates the association of oxidative stress with vascular inflammatory response in hyperglycemia through mechanisms 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. Role of the system in diabetes, however, remains largely unknown. The 26S proteasome is a large and a major protease complex of the system that degrades ubiquitinated proteins. Our laboratory provided the first evidence of its alteration in diabetes using a proteasome reporter mouse model. Specifically, we found that early hyperglycemia enhanced 26S proteasome functionality through peroxynitrite/superoxide-mediated proteasome activation, which elevated NF-κB-mediated endothelial inflammatory response in early diabetes. It becomes increasingly clear that the proteasome, often thought to be a constitutively active protease complex, is dynamically regulated to meet the changing proteolytic needs of a cell. Although the polyubiquitination of substrates is crucial to the specificity of degradation, extra mechanisms must exist to account for the plasticity of proteasome activity. 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. Consequently, we have begun to understand the significance of 26S proteasomes in diabetes, since the newly identified factors are being evaluated for their roles in the pathogenesis of diabetic complications, where responses to modulators, such as a stressor (e.g., hyperglycemia, hypoxia, excess nutrition, and caloric restriction) and/or an intervention (e.g., with pharmaceutical or naturally-occurring compounds) are being assessed. If successful, findings in these projects bear the promise to provide insights to the development of therapeutic strategies for diabetes and the 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
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.