Our goal is to understand the molecular mechanisms responsible for the initiation and prevention of calcification in the artery media. Our working hypothesis is that blood contains a causative agent(s) for medial artery calcification, and that the ability of this serum nucleator to initiate calcification in the elastic lamellae of the artery media is normally prevented by the opposing action of calcification inhibitors such as the vitamin K-dependent matrix Gla protein (MGP), an inhibitor which is secreted by smooth muscle cells adjacent to the elastic lamellae in the artery media. This blood borne theory of medial artery calcification predicts that calcification can occur in vivo whenever the initiation of medial calcification driven by the serum nucleator exceeds the capacity ofinhibitors such as MGP to prevent this calcification. Our initial study shows that serum contains a potent nucleator of elastin calcification, and that this agent is a 55-150kDa protein.
Our first aim i s to understand the serum nucleator of medial artery calcification, and we have designed experiments to identify the nucleator, to use recombinant nucleator in a variety of studies of nucleator structure-function, and to test the hypothesis that serum nucleator activity drives artery calcification in vivo.
Our second aim i s to understand the factors that determine the extent of medial calcification in the rat, and we have designed experiments to test the ability of bone resorption inhibitors to prevent medial calcification in uremia, and to arrest the progression of medial calcification once it has begun. We will also determine whether warfarin acts synergistically with uremia to accelerate medial calcification.
Our third aim i s to identify the molecular mechanisms by which medial artery calcification is normally prevented by matrix Gla protein. Pilot studies show that MGP is highly expressed by the artery in organ culture, that warfarin causes medial calcification in organ culture, and that addition of MGP to medium prevents this calcification. We have designed experiments using artery organ culture to determine the mechanisms by which MGP normally inhibits medial artery calcification; the relation between MGP structure and its activity as a calcification inhibitor; and the factors, which regulate MGP expression and phosphorylation by vascular cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058090-09
Application #
7324101
Study Section
Special Emphasis Panel (ZRG1-CVS-E (02))
Program Officer
Srinivas, Pothur R
Project Start
1998-07-01
Project End
2010-11-30
Budget Start
2007-12-01
Budget End
2010-11-30
Support Year
9
Fiscal Year
2008
Total Cost
$317,516
Indirect Cost
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
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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