This proposal focuses on a newly recognized metalloproteinase in the insulin-like growth factor (IGF) regulatory system in atherosclerosis. IGFs play a critical role in the vascular injury response through their potent effects on cell proliferation, migration, survival and extracellular matrix production within the developing intimal lesion. IGF binding proteins (IGFBPs) produced by vascular cells modulate local IGF bioactivity through their control of IGF interaction with specific cell surface receptors. In vitro studies have implicated an inhibitory IGFBP, IGFBP-4, and a specific IGFBP-4 protease (IGFBP4-ase), so-called pregnancy-associated plasma protein A (PAPP-A), in cellular response to injury, including vascular injury. By cleaving IGFBP-4 in a highly regulated manner, IGFBP4-ase/PAPPA increases the pericellular IGF available for receptor activation. In vivo, IGFBP4-ase/PAPP-A expression is induced in injured coronary arteries paralleling the formation of neointima. Recently, IGFBP4-ase/PAPP-A immunoreactivity was demonstrated in culprit plaques of humans who had died of myocardial infarction, with the most intense staining in the inflammatory shoulder associated with smooth muscle cells, macrophages, and T-lymphocytes. Our overall hypothesis is that IGFBP4- ase/PAPP-A is a key IGF regulatory factor in the vascular response to injury leading to atherosclerosis and promoting plaque vulnerability. Utilizing cultured human cells and genetically engineered mice, the SPECIFIC AIMS of this proposal are to: 1) Determine the mechanisms underlying elevated IGFBP4-ase/PAPP-A in vulnerable plaque. 2) Determine the effect of IGFBP4-ase/PAPP-A deficiency on the development and progression of atherosclerotic plaque. 3) Determine the effect of targeted IGFBP4-ase/PAPP-A expression on the development and progression of atherosclerotic plaque. These studies seek to gain a better understanding of the cellular and molecular biology of atherosclerosis in order to establish a scientific basis for novel strategies to identify and limit plaque development, progression, and instability.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL074871-01
Application #
6697149
Study Section
Endocrinology Study Section (END)
Program Officer
Wassef, Momtaz K
Project Start
2003-12-01
Project End
2007-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
1
Fiscal Year
2004
Total Cost
$368,750
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Bale, Laurie K; Chakraborty, Suban; Conover, Cheryl A (2014) Inducible reduction in pregnancy-associated plasma protein-A gene expression inhibits established atherosclerotic plaque progression in mice. Endocrinology 155:1184-7
Conover, Cheryl A; Bale, Laurie K; Powell, David R (2013) Inducible knock out of pregnancy-associated plasma protein-a gene expression in the adult mouse: effect on vascular injury response. Endocrinology 154:2734-8
Boldt, Henning B; Bale, Laurie K; Resch, Zachary T et al. (2013) Effects of mutated pregnancy-associated plasma protein-a on atherosclerotic lesion development in mice. Endocrinology 154:246-52
Bale, Laurie K; Resch, Zachary T; Harstad, Sara L et al. (2013) Constitutive expression of pregnancy-associated plasma protein-A in arterial smooth muscle reduces the vascular response to injury in vivo. Am J Physiol Endocrinol Metab 304:E139-44
Conover, Cheryl A (2013) Role of PAPP-A in aging and age-related disease. Exp Gerontol 48:612-3
Mader, Jessica R; Resch, Zachary T; McLean, Gary R et al. (2013) Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy. J Endocrinol 219:51-8
Conover, Cheryl A (2012) Key questions and answers about pregnancy-associated plasma protein-A. Trends Endocrinol Metab 23:242-9
Conover, Cheryl A; Mason, Megan A; Bale, Laurie K et al. (2010) Transgenic overexpression of pregnancy-associated plasma protein-A in murine arterial smooth muscle accelerates atherosclerotic lesion development. Am J Physiol Heart Circ Physiol 299:H284-91
Conover, Cheryl A (2010) PAPP-A: a new anti-aging target? Aging Cell 9:942-6
Conover, Cheryl A; Harrington, Sean C; Bale, Laurie K (2008) Differential regulation of pregnancy associated plasma protein-A in human coronary artery endothelial cells and smooth muscle cells. Growth Horm IGF Res 18:213-20

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