Arterial calcification commonly develops in association with atherosclerosis, aging, diabetes mellitus (DM), and renal failure and contributes to excess cardiovascular mortality and morbidity. In atherosclerosis, lesion intimal calcification is directly associated with leukocyte-mediated inflammation and modulated by oxidant stress via products of lipoprotein oxidation. In contrast, artery tunica media calcification may be more widely spread through the arterial tree, reflecting systemic changes in mediators of calcification. But common to both forms of artery calcification is altered differentiation of lesional cells, manifested by an active process with features resembling skeletal endochondral bone formation. Recently, we linked human """"""""idiopathic"""""""" infantile arterial calcification (IIAC) to deficiency of NPP1, which generates the physiologic calcification inhibitor PPi. IIAC is a spontaneous form of widely disseminated large artery media calcification and is commonly associated with periarticular calcifications, similar to findings in NPPl-deficient mice. Preliminary studies reveal chondroid metaplasia within aortic cells in situ and enhanced calcification by enriched (>95% a-actin positive) VSMCs from aortas of two mice with extracellular PPi depletion and remarkably similar pathologic skeletal calcification (i.e., NPP1 null mice and ank/ank mice in which the PPi channelling function of ANK is disabled). We will test the hypothesis that extracellular PPi depletion promotes artery calcification by a 2-step process of chondrogenesis, and chondrocytic maturation to hypertrophy in VSMCs and pluripotential cells in arteries, mediated by selective PPi-mediated changes in expression of the oxidant stress regulator vanin-1 -pantetheinase and by the inflammatory pro-atherogenic chemokine KC/GROa (CXCL1), respectively. Completion of these studies will link alterations in VSMC PPi metabolism with modulation of oxidant stress and chemokine responses pertinent to pathologic calcification in both degenerative disorders and atherosclerosis. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL077360-01
Application #
6811801
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Applebaum-Bowden, Deborah
Project Start
2004-07-01
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$246,750
Indirect Cost
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
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Zhao, Xianling; Petursson, Freyr; Viollet, Benoit et al. (2014) Peroxisome proliferator-activated receptor ? coactivator 1? and FoxO3A mediate chondroprotection by AMP-activated protein kinase. Arthritis Rheumatol 66:3073-82
Serrano, Ramon L; Yu, Weifang; Terkeltaub, Robert (2014) Mono-allelic and bi-allelic ENPP1 deficiency promote post-injury neointimal hyperplasia associated with increased C/EBP homologous protein expression. Atherosclerosis 233:493-502
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Neogi, Tuhina; George, Jacob; Rekhraj, Sushma et al. (2012) Are either or both hyperuricemia and xanthine oxidase directly toxic to the vasculature? A critical appraisal. Arthritis Rheum 64:327-38
Dammanahalli, K Jagadeesha; Stevens, Stephanie; Terkeltaub, Robert (2012) Vanin-1 pantetheinase drives smooth muscle cell activation in post-arterial injury neointimal hyperplasia. PLoS One 7:e39106
Nitschke, Yvonne; Weissen-Plenz, Gabriele; Terkeltaub, Robert et al. (2011) Npp1 promotes atherosclerosis in ApoE knockout mice. J Cell Mol Med 15:2273-83

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