This proposal focuses on a newly recognized zinc metalloproteinase in the insulin-like growth factor (IGF) regulatory system, so-called pregnancy-associated plasma protein-A (PAPP-A), and its role in atherosclerosis. IGFs play a critical role in the vascular injury response through their potent and varied receptor-mediated effects on proliferation, migration, survival and differentiated cell function. PAPP-A is secreted by and binds to vascular cells, and, by proteolytic cleavage of local inhibitory IGF binding proteins, can increase the pericellular IGF available for receptor activation within the developing lesion. Strong PAPP-A immunoreactivity co-localizing with activated smooth muscle cells and macrophages has been demonstrated in vulnerable plaques of humans who had died of myocardial infarction with little or no staining in stable plaques. In addition, elevated serum PAPP-A is under consideration as a biomarker of acute coronary syndro muscle show accelerated atherosclerotic lesion development. Our overall hypothesis is that PAPP-A is a key regulatory factor promoting atherosclerotic plaque development and plaque vulnerability. Utilizing novel transgenic and conditional gene knock-out mice, the SPECIFIC AIMS of this proposal are to: 1. Ascertain the structural determinants of PAPP-A necessary for its ability to enhance atherosclerotic plaque development. 2. Determine the effect of PAPP-A deficiency on established atherosclerotic plaque. 3. Determine the effect of PAPP-A overexpression on plaque vulnerability. The proposed studies seek to gain a better understanding of PAPP-A in the fundamental biology of atherosclerosis, and should establish a scientific basis for novel strategies to identify and limit, and possibly reverse, plaque growth and vulnerability in atherosclerosis.

Public Health Relevance

Atherosclerosis is the major cause of death in westernized societies. The proposed studies seek to gain a better understanding of a newly discovered enzyme implicated in atherosclerotic lesion development and should establish a scientific basis for novel strategies to identify and limit, and possibly reverse, atherosclerosis. ????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074871-08
Application #
8220837
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Liu, Lijuan
Project Start
2009-05-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
8
Fiscal Year
2012
Total Cost
$373,973
Indirect Cost
$126,473
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
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
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
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
Conover, Cheryl A; Harrington, Sean C; Bale, Laurie K et al. (2007) Surface association of pregnancy-associated plasma protein-A accounts for its colocalization with activated macrophages. Am J Physiol Heart Circ Physiol 292:H994-H1000
Boldt, Henning B; Conover, Cheryl A (2007) Pregnancy-associated plasma protein-A (PAPP-A): a local regulator of IGF bioavailability through cleavage of IGFBPs. Growth Horm IGF Res 17:10-8

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