Metabolic syndrome-diabetes represents a cluster of high risks for atherothrombosis (obesity, dyslipidemia, hypertension, insulin resistance) and is characterized by chronic and systemic inflammation that evolves eventually to atherosclerosis and thrombosis. A hallmark early event for the disease is endothelial injury that expresses and releases adhesion molecules, among them von Willebrand factor (VWF). VWF is the most widely used marker for endothelial injury, but much less studied for its adhesive properties and roles in the initiating and propagating atherothrombosis. This is despite the findings that mice deficient in VWF develop less atherosclerotic lesions. We have recently found that the activity of ADAMTS-13, which cleaves ULVWF to reduce its adhesiveness, is decreased in patients with severe systemic inflammation. The decrease is also observed in mice with hypercholesterolemia. We further find that ADAMTS-13 synthesis is severely reduced in the liver of diabetic mice. These preliminary results and published data have led us to hypothesize that ULVWF proteolysis is deficient or insufficient in metabolic syndrome due to persistent ULVWF release by inflamed endothelial cells and inhibition of ADAMTS-13 synthesis and activity. As a result, un- or partially cleaved ULVWF on endothelial cells tether and aggregate platelets and leukocytes that promotes endothelial injury and atherothrombosis. We proposed to test this hypothesis by clinical, animal, and in vitro studies to answer four specific questions. First, is ULVWF proteolysis deficient in metabolic syndrome as measure by ADAMTS-13 activity and the adhesive properties of plasma VWF? Second, does the deficiency correlate with the initiation and propagation of atherosclerotic lesions? Third, what causes the deficiency? We will specifically focus on the effects of inflammatory adipokines, soluble VWF, lipids, glucose, and insulin on ADAMTS-13 synthesis and activity. Fourth, can recombinant ADAMTS-13 reduce or delay the vascular injury and atherosclerotic lesions? For this, we will periodically administer recombinant ADAMTS-13 to mice that suffer obesity, hypercholesterolemia, and diabetes. The proposed studies will help us to understand the pathophysiology of metabolic syndrome-diabetes and its common atherothrombostic complications (and systemic inflammation). They will also provide new therapeutic target to treat and prevent the disease. PROJECT NARRATIVE: This is project is designed to study how proteolysis of ULVWF becomes deficient in conditions of metabolic syndrome-diabetes. It will investigate pathophysiological changes in ADAMTS-13 synthesis and activity in patients with metabolic syndrome- diabetes, in mice bearing components of this syndrome, and in a set of in vitro experiments. Results of the study will help us to understand how defective ULVWF proteolysis contributes to the development of atherothrombosis associated with the syndrome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL085769-05
Application #
8387669
Study Section
Special Emphasis Panel (ZRG1-HEME-C (02))
Program Officer
Sarkar, Rita
Project Start
2008-04-01
Project End
2013-12-31
Budget Start
2012-01-15
Budget End
2013-12-31
Support Year
5
Fiscal Year
2011
Total Cost
$382,018
Indirect Cost
Name
Puget Sound Blood Center
Department
Type
DUNS #
092881085
City
Seattle
State
WA
Country
United States
Zip Code
98104
Nascimbene, Angelo; Hilton, Tristan; Konkle, Barbara A et al. (2017) von Willebrand factor proteolysis by ADAMTS-13 in patients on left ventricular assist device support. J Heart Lung Transplant 36:477-479
Zhou, Yong; Qin, Shizhen; Hilton, Tristan et al. (2017) Quantification of Von Willebrand Factor Cleavage by adamts-13 in Patients Supported by Left Ventricular Assist Devices. ASAIO J 63:849-853
Zhang, Li-han; Yang, Ai-jun; Wang, Min et al. (2016) Enhanced autophagy reveals vulnerability of P-gp mediated epirubicin resistance in triple negative breast cancer cells. Apoptosis 21:473-88
Kamran, Hassan; Nambi, Vijay; Negi, Smita et al. (2016) Magnetic Resonance Venous Volume Measurements in Peripheral Artery Disease (from ELIMIT). Am J Cardiol 118:1399-1404
Song, Jaewoo; Xue, Cheng; Preisser, John S et al. (2016) Association of Single Nucleotide Polymorphisms in the ST3GAL4 Gene with VWF Antigen and Factor VIII Activity. PLoS One 11:e0160757
Tian, Ye; Salsbery, Breia; Wang, Min et al. (2015) Brain-derived microparticles induce systemic coagulation in a murine model of traumatic brain injury. Blood 125:2151-9
Yuan, Hengjie; Houck, Katie L; Tian, Ye et al. (2015) Piperlongumine Blocks JAK2-STAT3 to Inhibit Collagen-Induced Platelet Reactivity Independent of Reactive Oxygen Species. PLoS One 10:e0143964
Song, Jaewoo; Chen, Fengju; Campos, Marco et al. (2015) Quantitative Influence of ABO Blood Groups on Factor VIII and Its Ratio to von Willebrand Factor, Novel Observations from an ARIC Study of 11,673 Subjects. PLoS One 10:e0132626
Liu, Xiao; Li, Ying; Zhu, Hui et al. (2015) Use of non-contact hopping probe ion conductance microscopy to investigate dynamic morphology of live platelets. Platelets 26:480-5
Wang, Rui; Stone, Rebecca L; Kaelber, Jason T et al. (2015) Electron cryotomography reveals ultrastructure alterations in platelets from patients with ovarian cancer. Proc Natl Acad Sci U S A 112:14266-71

Showing the most recent 10 out of 19 publications