Jian Xu, Ph.D.

Position: Associate Professor of Medicine, Department of Internal Medicine, Diabetes Research Member

Biography

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. Deregulated 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 deregulated 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.

Email

Additional Websites

Health Education

Graduate School
Postdoctoral Fellow, Diabetic Complications University of Oklahoma Health Sciences Center
Oklahoma City, OK
Postdoctoral Fellow, Cardiovascular Diseases University of Tennessee Medical Center
Knoxville, TN
PhD, Biochemical Pharmacology University of Konstanz
Konstanz, Germany,
Master Degree, Biochemistry Xinjiang Agricultural University
Urumqi, China,

Undergraduate School
Bachelor Degree, Biology Shaanxi Normal University
Xi'an, China,

Notable Work

Research Interests

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.

Publications

Frontiers in Cardiovascular Medicine 2018
Endothelial–vascular smooth muscle cells interactions in atherosclerosis. PMID: 30406116 PMCID: PMC6207093
Frontiers in Chemistry (Chemical Biology) 2018
Ubiquitin receptor RPN13 mediates the inhibitory interaction of diphenyldihaloketones CLEFMA and EF24 with the 26S proteasome. PMID: 30280096.
Frontiers in Chemistry (Chemical Biology) 2018
Ubiquitin receptor RPN13 mediates the inhibitory interaction of diphenyldihaloketones CLEFMA and EF24 with the 26S proteasome. 6 (392), 1-13. PMID: 30280096.
Journal of Clinical Investigation 2018
Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes. 128(9), 4025-4043. PMID: 30102256.
Frontiers in Cardiovascular Medicine 2017
Vascular endothelial regulation of obesity-associated insulin resistance. Aug 9; 4:51. PMID: 28848738 PMCID: PMC5552760
Autophagy 2016
Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy (3rd edition) 12(1) 1-222. PMID: 26799652
American Diabetes Association's 75th Scientific Sessions 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 Tour).
American Diabetes Association's 75th Scientific Sessions, June 5-9, 2015, Boston, MA 2015
A New Mediator of SIRT1 Protein Turnover Regulated by Endothelial Nitric Oxide. (this abstract has also been selected to be showcased in aGuided Audio Poster Tour).
American Diabetes Association's 74th Scientific Sessions 2014
LC3B-mediated Degradation of the Vascular Endothelial Growth Factor Receptor 2 Impaired Angiogenesis in Diabetes.
American Diabetes Association's 74th Scientific Sessions 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)
PLoS One 2014
Upregulation of Unc-51-like kinase 1 by nitric oxide stabilizes SIRT1, independent of autophagy. 9(12):e116165. PMID: 25541949. PMCID: PMC4277463
Cardiovascular Research 2014
Proteasomal degradation of O-GlcNAc transferase elevates hypoxia-induced vascular endothelial inflammatory response. 103(1):131-139. PMID: 24788415. PMCID: PMC4133591
Carbohydr Polym 2014
Chitosan oligosaccharides block LPS-induced O-GlcNAcylation of NF-?B and endothelial inflammatory response. 2014; 99:568-78. PMCID: PMC3843148
American Heart Association's 2013 Scientific Sessions 2013
Proteasomal Degradation of O-GlcNAc Transferase Enhances Hypoxia-Mediated Vascular Endothelial Inflammatory Response. November 16-20, Dallas, TA
American Diabetes Association's 73rd Scientific Sessions 2013
The Endothelial Nitric Oxide Synthase Derived Nitric Oxide Regulates Vascular 26S Proteasome Functionality. June 21-25, 2013 in Chicago, IL
American Heart Association's 2013 Scientific Sessions, November 16-20, Dallas, TA 2013
Proteasomal Degradation of O-GlcNAc Transferase Enhances Hypoxia-Mediated Vascular Endothelial Inflammatory Response.
PLoS ONE 2012
Angiogenesis impairment in diabetes: Role of methylglyoxal-induced receptor for advanced glycation endproducts, autophagy and vascular endothelial growth factor receptor 2. 7(10):e46720. PMID: 23056421. PMCID: PMC3463541
Arteriosclerosis, Thrombosis, and Vascular Biology 2012
Enhancement of 26S proteasome functionality connects oxidative stress and vascular endothelial inflammatory response in diabetes. 32 (9):2131-2140. PMID: 22772755.
PLoS One 2012
Regulation of the proteasome by AMPK in endothelial cells: the role of O-GlcNAc transferase (OGT). 7(5):e36717.
PLoS One 2012
PA700 nitration links proteasome activation to endothelial dysfunction in mouse models of cardiovascular risk factors. 7(1):e29649.
Arteriosclerosis, Thrombosis, and Vascular Biology 2011
Activation of NAD(P)H oxidases by thromboxane A2 receptor uncouples endothelial nitric oxide synthase. 31(1):125-132.
The American Society of Nephrology 2011 Meetings Philadelphia, PA 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 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.
American Diabetes Association's 71st Scientific Sessions, 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).
Central RegionIDEAConference 2011
Hyperglycemia activates 26S proteasome in STZ-treated mice. Omaha, NE, May 23-25, 2011. (*Corresponding author and selected as an oral presentation).
The American Society of Nephrology 2011 Meetings Philadelphia, PA 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 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.
American Diabetes Association's 71st Scientific Sessions 2011
Hyperglycemia induced 26S proteasome activation is an early event in streptozotocin-treated mice.
Central RegionIDEAConference. Omaha, NE, May 23-25, 2011. 2011
Hyperglycemia activates 26S proteasome in STZ-treated mice.
Circulation Research 2010
AMPKalpha2 causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: role of 26S proteasomes.106(6):1117-28.
Circulation 2009
Molecular Insights and Therapeutic Targets for Diabetic Endothelial Dysfunction.120(13):1266-86.
Hypertension 2009
Tyrosine nitration of PA700 activates 26S proteasomes to induce endothelial functions in angiotensin II-induced hypertension.54:625-632.
J Biol Chem 2009
Thromboxane A2 receptor activates a Rho-associated kinase/LKB1/PTEN pathway to attenuate endothelium insulin signaling. 284:17120-17128.
Hypertension 2008
Acute Inhibition of GTP Cyclohydrolase 1 Uncouples Endothelial Nitric Oxide Synthase and Elevates Systolic Blood Pressure. 52(3):484-90.
J Cell Mol Med 2008
Activation of Protease Calpain by Oxidized and Glycated LDL Increases the Degradation of Endothelial Nitric Oxide Synthase. Jun 28. [Epub ahead of print]
J Biol Chem 2008
Reactive Nitrogen Species Is Required for the Activation of the AMP-activated Protein Kinase by Statin in Vivo. Jul 18;283(29):20186-97.
J Biol Chem 2008
Protein kinase C zeta -dependent LKB1 serine 428 phosphorylation increases LKB1 nucleus export and apoptosis in endothelial cells. 283(18):12446-55.
Circulation Research102 2008
Thromboxane receptor via hydrogen peroxide activates the AMP-activated kinase in vascular smooth muscle cells.102(3):328-37.
Atherosclerosis 2008
Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus. 198(1):65-76.
Circulation 2007
Reactive nitrogen species induced by hyperglycemia suppresses Akt signaling and triggers apoptosis by upregulating phosphatase PTEN in an LKB1-dependent manner. 116 (14): 1585-95.
Circulation 2007
Proteasome-dependent degradation of guanosine 5-triphosphate cyclohydrolase I causes tetrahydrobiopterin deficiency in diabetes mellitus.Circulation. 116 (8): 944-53.
Journal of Biological Chemistry 2007
Activation of protein phosphoatase PP2A by palmitic acid inhibits the AMP-activated protein kinase (AMPK). 30; 282(13):9777-9788.
Arteriosclerosis, Thrombosis, and Vascular Biology 2006
Uncoupling of endothelial nitric oxide synthase by Hypochlorous acid. Role of vascular NAD(P)H oxidase-derived superoxide and peroxynitrite. 26(12):2688-2695.
Arteriosclerosis, Thrombosis, and Vascular Biology 2006
Rabelink TJ and von Zonneveld AJ: Coupling eNOS uncoupling to the innate immune response.Arteriosclerosis, Thrombosis, and Vascular Biology.26(12):2585-2587, 2006.
Diabetes 2006
Endothelial nitric oxide synthase-dependent tyrosine nitration of prostacyclin synthase in diabetes mellitus in vivo. 55(11):3133-3141.
Diabetes
In VivoActivation of AMP-activated Protein Kinase Attenuates Diabetes-enhanced Degradation of GTP Cyclohydrolase I.58(8):1893-901.