Arterial calcification is a phenotype of vascular repair in atherosclerosis, diabetes, hyperphosphatemic renal failure, and aging that promotes mortality. Arterial calcification is an active and organized process, switched on by chondrocytic and osteoblastic differentiation of intra-arterial progenitors. Chondrogenesis is modulated by the metabolism of GSH. Vanin-1 pantetheinase suppresses GSH synthesis. Vanin-1 is induced by a variety of inflammatory stressors and promotes granuloma formation and intestinal inflammation. Vanin-1 suppresses PPARgamma expression and signaling, and vanin-1 thereby "licenses" pro-inflammatory cytokine expression. We observe increased chondrogenic potential of mesenchymal precursor cells linked with both PPi deficiency and driven by increased vanin-1 pantetheinase activity, cysteamine generation, and consequent GSH depletion. Vanin-1 knockout also blunts phosphate donor-induced chondrogenic differentiation and calcification in PPi-deficient arterial explants. PPARgamma suppresses bone formation and inhibits calcification by vascular cells. PPARgamma agonism also blunts experimental aortic media calcification. Our core hypothesis is that vanin-1 and modulation of PPARgamma are central and linked threads by which PPi/Pi imbalance, bone morphogens, and inflammation drive intra- arterial chondro-osseous differentiation and distinct phenotypes of primarily intimal or tunica media calcification. Here, we specifically aim to: 1. Define the core paracrine and autocrine mechanisms by which vanin-1 promotes switching on chondrogenic trans- differentiation in arterial SMCs. 2. Test the hypothesis that vanin-1 deficiency delays or prevents intra-arterial chondrogenesis and lethal artery media calcification in MGP deficient mice. 3. Test the hypothesis that SMC PPARgamma deficiency is sufficient to increase artery calcification in MGP deficient mice without primary dysregulation of vanin-1. 4. Test the hypothesis that generalized vanin-1 deficiency and SMC-specific PPARgamma deficiency exert opposite effects on atherosclerotic lesion calcification in chow-fed, aged apoE ko mice. Completion of these studies will provide novel insight and identification of vanin-1 as a potential new therapeutic target for arterial calcification.

Public Health Relevance

Lay summary Arterial calcification is one of the potential outcomes of blood vessel repair in atherosclerosis, diabetes, chronic kidney disease, and aging. Artery calcification promotes mortality in these conditions and our objective is to identify new targets for therapies. In this project, we will define and test proposed mechanisms whereby linked changes in an enzyme (Vanin-1) involved in defense against oxidative stress, and the gene expression regulator PPARgamma, promote arterial calcification by switching on cartilage and bone formation in diseased arteries.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077360-08
Application #
8291308
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Fleg, Jerome
Project Start
2004-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2012
Total Cost
$315,414
Indirect Cost
$92,664
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
Terkeltaub, Robert (2014) Apolipoprotein a-I at the interface of vascular inflammation and arthritis. Arterioscler Thromb Vasc Biol 34:474-6
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
Nitschke, Yvonne; Baujat, Genevieve; Botschen, Ulrike et al. (2012) Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet 90:25-39
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
Yu, Weifang; Liu-Bryan, Ru; Stevens, Stephanie et al. (2012) RAGE signaling mediates post-injury arterial neointima formation by suppression of liver kinase B1 and AMPK activity. Atherosclerosis 222:417-25
Rutsch, Frank; Nitschke, Yvonne; Terkeltaub, Robert (2011) Genetics in arterial calcification: pieces of a puzzle and cogs in a wheel. Circ Res 109:578-92
Neogi, Tuhina; Terkeltaub, Robert; Ellison, R Curtis et al. (2011) Serum urate is not associated with coronary artery calcification: the NHLBI Family Heart Study. J Rheumatol 38:111-7
Cecil, Denise L; Terkeltaub, Robert A (2011) Arterial calcification is driven by RAGE in Enpp1-/- mice. J Vasc Res 48:227-35
Polewski, Monika D; Johnson, Kristen A; Foster, Melissa et al. (2010) Inorganic pyrophosphatase induces type I collagen in osteoblasts. Bone 46:81-90

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