The objectives of this investigation are to define the contribution of warfarin treatment and of dietary vitamin K deficiency to the arterial calcification process in humans and in a rat model of the disease. The Principal Investigator will assess the molecular mechanism by which matrix Gla proteins, which are vitamin K dependent, can inhibit the arterial calcification process. The applicant will identify those risk factors which act synergistically with warfarin to accelerate arterial calcification in a rat model. He will establish the extent to which arterial calcification is arrested or reversed. Within the context of this specific aim, he will investigate the effect of dietary deficiency on the carboxylation of the Gla protein and the calcification in arteries in the rat. Dr. Price will also determine the effect of warfarin on the calcification of the intima in animal models of atherosclerosis and investigate the ability of the Gla protein infusion the arterial calcification that is induced by warfarin.
The second aim, is designed to investigate the relationship between defective carboxylation of serum Gla protein and arterial calcification using isoelectric focusing and terminal protein sequencing; mineral binding activity will be done to measure carboxylation status. He will also look at the structure and functional associations of Gla protein and calcification sites in the human artery. The principal investigator will also investigate the mechanism by which the Gla proteins inhibit the calcification of elastin in the human aortic media when elastin is added to solutions that contain physiological concentrations of calcium and phosphate. He will also determine the role of Gla protein as an inhibitor of the growth of crystallites isolated by the human aortic media. These experiments are being done to establish the importance of vitamin K deficiency and of warfarin treatment as risk factors for the calcification of human arteries.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058090-03
Application #
6184373
Study Section
Pathology A Study Section (PTHA)
Project Start
1998-07-01
Project End
2003-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
3
Fiscal Year
2000
Total Cost
$326,060
Indirect Cost
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Viegas, Carla S B; Cavaco, Sofia; Neves, Pedro L et al. (2009) Gla-rich protein is a novel vitamin K-dependent protein present in serum that accumulates at sites of pathological calcifications. Am J Pathol 175:2288-98
Shea, M K; Benjamin, E J; Dupuis, J et al. (2009) Genetic and non-genetic correlates of vitamins K and D. Eur J Clin Nutr 63:458-64
Toroian, Damon; Price, Paul A (2008) The essential role of fetuin in the serum-induced calcification of collagen. Calcif Tissue Int 82:116-26
Viegas, Carla S B; Simes, Dina C; Laize, Vincent et al. (2008) Gla-rich protein (GRP), a new vitamin K-dependent protein identified from sturgeon cartilage and highly conserved in vertebrates. J Biol Chem 283:36655-64
Shea, M Kyla; Booth, Sarah L; Massaro, Joseph M et al. (2008) Vitamin K and vitamin D status: associations with inflammatory markers in the Framingham Offspring Study. Am J Epidemiol 167:313-20
Toroian, Damon; Lim, Joo Eun; Price, Paul A (2007) The size exclusion characteristics of type I collagen: implications for the role of noncollagenous bone constituents in mineralization. J Biol Chem 282:22437-47
Hamlin, N J; Ong, K G; Price, P A (2006) A serum factor that recalcifies demineralized bone is conserved in bony fish and sharks but is not found in invertebrates. Calcif Tissue Int 78:326-34
Price, Paul A; Chan, Wai Si; Jolson, Dawn M et al. (2006) The elastic lamellae of devitalized arteries calcify when incubated in serum: evidence for a serum calcification factor. Arterioscler Thromb Vasc Biol 26:1079-85
O'Donnell, Christopher J; Shea, M Kyla; Price, Paul A et al. (2006) Matrix Gla protein is associated with risk factors for atherosclerosis but not with coronary artery calcification. Arterioscler Thromb Vasc Biol 26:2769-74
Price, Paul A; June, Helen H; Hamlin, Nicholas J et al. (2004) Evidence for a serum factor that initiates the re-calcification of demineralized bone. J Biol Chem 279:19169-80

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