Calcification is ubiquitous in vascular disease, and contributes significantly to morbidity and mortality. Matrix GLA protein (MGP) is an alleged calcification inhibitor that is up-regulated in atherosclerotic lesions. Deletion of the MGP gene results in arterial calcification and in morphological abnormalities in mice and humans. MGP is a secreted protein that is modified by vitamin K-dependent g-carboxylation. When isolated from bone, it is processed and lacks seven C-terminal amino acids. The mechanism of MGP is poorly understood. However, our experimental data points to a role in transforming growth factor-fi (TGF-fi) and bone morphogenetic protein (BMP) signaling. The data suggest a potential link between BMP and TGF-li in that BMP2 and BMP-4 induce expression of the TGF-R, receptor Activin-like Kinase receptor 1 (ALK1). Signaling through ALK1 induces MGP, which provides negative feedback regulation for BMP. Interactions between MGP and specific receptors were also observed. Three hypotheses will be tested in this grant. The first hypothesis is that MGP regulates TGF-fi and BMP signaling at the receptor level, resulting in altered SMAD signaling and gene expression. We will characterize activation of SMAD signaling and relevant reporter genes induced by TGF-li1, BMP-2 and BMP-4 in presence of MGP, and identify the TGF-li / BMP receptors that are regulated by MGP. The second hypothesis is that MGP participates in specific protein-protein interactions that may be altered by C-terminal processing. We will characterize the interactions, which include the TGF-ft receptors, using specific immunoprecipitations in combination with a general proteomic approach. The third hypothesis is that MGP functions as a BMP inhibitor in developing arteries and in atherosclerotic lesions. We will generate a transgenic mouse for targeted, conditional expression of the BMP-inhibitor Noggin. Noggin expression will be induced in MGP null mice in attempt to replace MGP and abolish calcification. The effect of Noggin will also be determined in atherosclerotic lesions in LDL-receptor null mice. Our results will add insight to calcification of vessels and heart valves, a common problem in heart disease. In addition, it may provide information on how to design new treatments for unwanted calcification.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081397-05
Application #
7766994
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Srinivas, Pothur R
Project Start
2006-04-24
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
5
Fiscal Year
2010
Total Cost
$375,049
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Yao, Jiayi; Guihard, Pierre J; Wu, Xiuju et al. (2017) Vascular endothelium plays a key role in directing pulmonary epithelial cell differentiation. J Cell Biol 216:3369-3385
Guihard, Pierre J; Yao, Jiayi; Blazquez-Medela, Ana M et al. (2016) Endothelial-Mesenchymal Transition in Vascular Calcification of Ins2Akita/+ Mice. PLoS One 11:e0167936
Boström, Kristina I; Yao, Jiayi; Guihard, Pierre J et al. (2016) Endothelial-mesenchymal transition in atherosclerotic lesion calcification. Atherosclerosis 253:124-127
Boström, Kristina I (2016) Where do we stand on vascular calcification? Vascul Pharmacol 84:8-14
Yao, Jiayi; Guihard, Pierre J; Blazquez-Medela, Ana M et al. (2016) Matrix Gla protein regulates differentiation of endothelial cells derived from mouse embryonic stem cells. Angiogenesis 19:1-7
Boström, Kristina I; Guihard, Pierre; Blazquez Medela, Ana M et al. (2015) Matrix Gla protein limits pulmonary arteriovenous malformations in ALK1 deficiency. Eur Respir J 45:849-52
Demer, Linda L; Boström, Kristina I (2015) Conflicting forces of warfarin and matrix gla protein in the artery wall. Arterioscler Thromb Vasc Biol 35:9-10
Jumabay, Medet; Boström, Kristina I (2015) Dedifferentiated fat cells: A cell source for regenerative medicine. World J Stem Cells 7:1202-14
Blazquez-Medela, Ana M; Guihard, Pierre J; Yao, Jiayi et al. (2015) ABCC6 deficiency is associated with activation of BMP signaling in liver and kidney. FEBS Open Bio 5:257-63
Jumabay, Medet; Moon, Jeremiah H; Yeerna, Huwate et al. (2015) Effect of Diabetes Mellitus on Adipocyte-Derived Stem Cells in Rat. J Cell Physiol 230:2821-8

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