MOLECULAR DETERMINANTS OF THE STABILITY OF ATHEROMA

Brigham And Women'S Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The arterial extracellular matrix critically influences the stability of atheroma. Accumulating evidence has demonstrated that rupture of vulnerable atherosclerotic plaques causes most acute coronary syndromes. Activated macrophages in human atheroma overexpress matrix-degrading enzymes including collagenases (MMP-1/collagenase-1 and MMP-13/collagenase-3). Such macrophage-derived collagenolytic activity in human coronary atheroma likely contributes to plaque vulnerability. However, direct in vivo evidence of the importance of collagen degradation due to collagenolytic enzymes in plaque disruption remains scant. We therefore propose to study in vivo mechanisms of collagen remodeling by collagenase in atherosclerosis prone mice. This project will test three hypotheses in vivo in genetically-altered mice. Specific Aim 1 will test the hypothesis that collagen degradation by collagenases plays a pivotal role in arterial remodeling during atherogenesis using genetically altered mice. We will determine whether collagenase resistance due to mutation of collagen type I at the cleavage site for collagenases increases collagen accumulation in atheroma induced by an atherogenic diet in atherosclerosis-susceptible, apolipoprotein E-deficient mice (apoE-/-). Specific Aim 2 will further test the hypothesis that collagenase plays a critical role in collagen breakdown in atheroma using another mouse model with targeted deletion of the major murine interstitial collagenase. We will determine whether collagenase (MMP-13) deficiency increases collagen accumulation in atheroma of hypercholesterolemic mice. Specific Aim 3 will explore the roles of blood cell (primarily macrophage)-derived collagenase (MMP-13) in collagen accumulation in atheroma. We hypothesize that selective restoration of collagenase activity in atherosclerosis-susceptible mice (MMP-13-/- / apoE -/-) by transfer of bone marrow from wild-type mice (MMP-13+/+ / apoE-/- into MMP-13-/- / apoE-/-) will decrease collagen content and thin the fibrous cap in diet-induced lesions. We will also determine whether selective deletion of MMP-13 in endothelial cells or smooth muscle cells will affect collagen remodeling in atheroma using Cre/loxP technology. Together, these in vivo experiments should help in understanding the mechanisms of extracellular matrix remodeling and destabilization of the plaque and provide important information for developing more specific and effective therapeutic strategies for the prevention of acute coronary events in patients. We aim by the end of the completion of the proposed project to have taken the concept of the dynamic nature of the plaque's extracellular matrix and the role of inflammatory signaling in regulating determinants of plaque stability from hypothesis to rigorous and definitive validation in vivo.