Activated cells in human coronary atheromata express high levels of matrix-degrading enzymes, e.g., collagenases and elastases. Our previous studies suggested that such collagenolytic and elastolytic activities regulate the integrity of diseased arteries. A series of recent studies supported by this NIH R01 provided the direct in vivo evidence for the important role of collagenolytic enzymes of the matrix metalloproteinase (MMP) family in arterial remodeling. This renewal application proposes to examine further the effects of genetic and pharmacologic manipulations of collagenases on plaque collagen metabolism, and to study in depth the role of elastolytic enzymes in arterial disease. We will also explore the possibility of detecting matrix degradation using biomarkers.
Specific Aim 1 will complete our studies of the roles of various interstitial collagenases in the regulation of the structure of atherosclerotic plaques in mice. We will examine the effects of deficiency of another collagenase MMP-8 on plaque structure. We will further analyze collagen structure in atheromata of the compound mutant mice lacking two major collagenases MMP-13 and MMP-8. Studies using a novel imaging technology and an MMP-13 selective inhibitor will test the hypothesis that pharmacologic inhibition of this collagenase will alter the plaque structure.
Specific Aim 2 will test the hypothesis that mice with combined deficiency of apoE and Niemann Pick disease, type C1 (NPC1) protein will show heightened susceptibility to arterial ectasia. As compound mutant apoE- and NPC1-deficient mice overexpress cathepsin K, a potent elastase, we will track cathepsin activity in vivo in these animals by molecular imaging. We will also image and characterize the structure of elastin in arterial tissue from these manipulated mutant mice.
Specific Aim 3 will develop and validate biomarkers of extracellular matrix protein degradation to provide novel tools to probe elastin and collagen degradation in vivo. These markers will include MSGC measurement of post-translationally modified amino acids and their condensates that serve as signatures for elastin and collagen breakdown. Exploration of the in vivo utility of novel markers of elastinolysis will use biological specimens derived from mice with mutations in various elastases including cathepsins K and S, MMP-9 and -12, and neutrophil elastase, as well as from mice with genetically-induced cardiomyopathies. If we succeed in developing and validating novel biomarkers, we will apply them to banks of blood specimens on patients in various large clinical trials conducted at our institution to test the hypothesis that the interventions (e.g. mineralocorticid receptor blocking agent or statin administration) affect matrix metabolism in humans in vivo.

Public Health Relevance

Collagenolytic and elastolytic activities in human coronary atheromata likely regulate the matrix structure of atherosclerotic plaques, a key determinant of the acute thrombotic complications. Our recent studies supported by this NIH R01 provided the direct in vivo evidence for the important role of collagenolytic enzymes. This renewal application proposes to examine further the effects of pharmacologic and genetic manipulations of collagenases on plaque collagen metabolism. We also propose to study in depth the role of elastolytic enzymes in the pathogenesis of arterial disease. In addition, we will explore the possibility of detecting matrix degradation using biomarkers. This project should help in understanding the mechanisms of arterial remodeling during atherogenesis. These complementary studies will translate further preclinical findings into clinical preventive cardiovascular medicine.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080472-07
Application #
8268487
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Ershow, Abby
Project Start
2005-04-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
7
Fiscal Year
2012
Total Cost
$424,223
Indirect Cost
$176,723
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Quillard, Thibaut; Ara├║jo, Haniel Alves; Franck, Gregory et al. (2014) Matrix metalloproteinase-13 predominates over matrix metalloproteinase-8 as the functional interstitial collagenase in mouse atheromata. Arterioscler Thromb Vasc Biol 34:1179-86
Libby, Peter; Lichtman, Andrew H; Hansson, Goran K (2013) Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity 38:1092-104

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