Prevention of vascular calcification is mediated in part by Matrix Gla Protein (MGP) and the hepatic ABC transporter C6 (AbccG). MGP is a secreted matrix protein and may affect vascular calcification in vivo by binding bone morphogenetic proteins (BMP) and/or calcium through gamma-carboxylated glutamates. Our data show that in vascular cells BMP-2/4 induce expression of the activin-like kinase receptor 1 (ALK1), an essential TGF-3 receptor in vascular development. ALK1 is also expressed in atherosclerotic lesions and promotes aggregation and proliferation of cultured lesion cells. Induction of the ALK1 receptor allows BMP- 2/4 to regulate expression of vascular endothelial growth factor and MGP, which provides a feed back loop to limit BMP-activity. The importance of this pathway in atherogenesis is unknown. Abcc6 is a membrane transporter that is mainly expressed in the liver. AbccG was identified in our previous studies using an integrative genomics approach, and was shown to protect against vascular calcification. Abcc6 deficiency has been associated with pseudoxanthoma elasticum that is characterized by progressive calcification and accelerated atherosclerosis. The site and the mechanism of action of Abcc6 are not understood. This application focuses on the mechanisms by which MGP and Abcc6 prevent vascular calcification, and the effect of ALK1 and Abcc6 on atherogenesis.
Four specific aims will be addressed.
In Specific Aim 1; we will determine the importance of BMP-binding versus calcium-binding for the ability of MGP to inhibit vascular calcification in vivo using homologous recombination in mice.
In Specific Aim 2, we will identify the receptor(s) and signaling pathway(s) that are required for BMP-2/4 to induce expression of the ALK1- receptor using siRNA, dominant negative receptors and molecular inhibitors in vitro.
Specific Aim 3 will address Abcc6 and Abcc6 related pathways and determine the site and the molecular basis of its inhibitory effect on vascular calcification using both in vitro and in vivo techniques. Finally, in Specific Aim 4, we will address the effects of modulating expression of ALK1 and Abcc6 on lesion development in established mouse models of atherosclerosis.

Public Health Relevance

Our studies are relevant to the prevention of vascular calcification, so-called hardening of the arteries, which contributes to the severity of heart disease. Information gained from our studies may aid in the design of new treatments for vascular calcification.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL030568-26A1
Application #
7647663
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
26
Fiscal Year
2009
Total Cost
$360,476
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Lang, Jennifer M; Pan, Calvin; Cantor, Rita M et al. (2018) Impact of Individual Traits, Saturated Fat, and Protein Source on the Gut Microbiome. MBio 9:
McDonald, Austin I; Shirali, Aditya S; Aragón, Raquel et al. (2018) Endothelial Regeneration of Large Vessels Is a Biphasic Process Driven by Local Cells with Distinct Proliferative Capacities. Cell Stem Cell 23:210-225.e6
Roberts, Adam B; Gu, Xiaodong; Buffa, Jennifer A et al. (2018) Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med 24:1407-1417
Zhu, W; Buffa, J A; Wang, Z et al. (2018) Flavin monooxygenase 3, the host hepatic enzyme in the metaorganismal trimethylamine N-oxide-generating pathway, modulates platelet responsiveness and thrombosis risk. J Thromb Haemost 16:1857-1872
Olde Loohuis, Loes M; Mangul, Serghei; Ori, Anil P S et al. (2018) Transcriptome analysis in whole blood reveals increased microbial diversity in schizophrenia. Transl Psychiatry 8:96
Mukherjee, Pallavi; Hough, Greg; Chattopadhyay, Arnab et al. (2018) Role of enterocyte stearoyl-Co-A desaturase-1 in LDLR-null mice. J Lipid Res 59:1818-1840
Orozco, Luz D; Farrell, Colin; Hale, Christopher et al. (2018) Epigenome-wide association in adipose tissue from the METSIM cohort. Hum Mol Genet 27:1830-1846
Erbilgin, Ayca; Seldin, Marcus M; Wu, Xiuju et al. (2018) Transcription Factor Zhx2 Deficiency Reduces Atherosclerosis and Promotes Macrophage Apoptosis in Mice. Arterioscler Thromb Vasc Biol 38:2016-2027
Boström, Kristina I; Yao, Jiayi; Wu, Xiuju et al. (2018) Endothelial Cells May Have Tissue-Specific Origins. J Cell Biol Histol 1:
Norheim, Frode; Bjellaas, Thomas; Hui, Simon T et al. (2018) Genetic, dietary, and sex-specific regulation of hepatic ceramides and the relationship between hepatic ceramides and IR. J Lipid Res 59:1164-1174

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