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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Ershow, Abby
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Brigham and Women's Hospital
United States
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Libby, Peter; Loscalzo, Joseph; Ridker, Paul M et al. (2018) Inflammation, Immunity, and Infection in Atherothrombosis: JACC Review Topic of the Week. J Am Coll Cardiol 72:2071-2081
Franck, Grégory; Mawson, Thomas L; Folco, Eduardo J et al. (2018) Roles of PAD4 and NETosis in Experimental Atherosclerosis and Arterial Injury: Implications for Superficial Erosion. Circ Res 123:33-42
Libby, Peter; Molinaro, Roberto; Sellar, Rob S et al. (2018) Jak-ing Up the Plaque's Lipid Core…and Even More. Circ Res 123:1180-1182
Michel, Jean-Baptiste; Libby, Peter; Franck, Grégory (2018) Internal Bleeding: Is Intraplaque Hemorrhage a Decoration or a Driver? JACC Basic Transl Sci 3:481-484
Folco, Eduardo J; Mawson, Thomas L; Vromman, Amélie et al. (2018) Neutrophil Extracellular Traps Induce Endothelial Cell Activation and Tissue Factor Production Through Interleukin-1? and Cathepsin G. Arterioscler Thromb Vasc Biol 38:1901-1912
Geovanini, Glaucylara Reis; Wang, Rui; Weng, Jia et al. (2018) Elevations in neutrophils with obstructive sleep apnea: The Multi-Ethnic Study of Atherosclerosis (MESA). Int J Cardiol 257:318-323
Libby, Peter; Ebert, Benjamin L (2018) CHIP (Clonal Hematopoiesis of Indeterminate Potential). Circulation 138:666-668
Libby, Peter (2017) Interleukin-1 Beta as a Target for Atherosclerosis Therapy: Biological Basis of CANTOS and Beyond. J Am Coll Cardiol 70:2278-2289
Jaiswal, Siddhartha; Natarajan, Pradeep; Silver, Alexander J et al. (2017) Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med 377:111-121
Aikawa, Elena; Libby, Peter (2017) A Rock and a Hard Place: Chiseling Away at the Multiple Mechanisms of Aortic Stenosis. Circulation 135:1951-1955

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