Molecular biology and mechanics of cardiac interstitium

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Acute coronary occlusion (CO) results in myocyte cell death and degradation of the extracellular matrix. Most patients who survive a myocardial infarction (Ml) have a residual scar. We will test the hypothesis that: "Collagen degradation within the first 48 h after coronary occlusion by changing the mechanical properties of the infarcted myocardium influences the ensuing collagen synthesis within the evolving scar and thus, determines the early (3 week) and late (6 week) structure and function of the ventricular scar". We plan to: 1) characterize factors involved in the early activation of matrix metalloproteinases (MMPs) and collagen degradation in the setting of CO including the mechanical activation of MMPs, plasmin and tumor necrosis factor-a (TNF-a), 2) determine the relationship between the extent of early collagen degradation and the material properties of the infarcted area and, 3) determine the relationship between local deformation in the evolving scar and collagen synthesis in the healing tissue. We will examine the following aims. Aim 1. MMP induced collagen degradation within 48 h after CO is due to TNF-a, stretch, plasmin dependent and independent inducing/activating actions on MMPs and to the mechanical disruption of collagen fibers. We will use various pharmacological approaches following CO in pigs to determine the role of mechanical distention, plasmin and TNF-a have on modulating collagen breakdown products and MMP activity in serum and in myocardial samples. Aim 2. Collagen degradation within 48 h after CO determines th6 structural and functional properties of the immature (3 week) collagenous scar and the ensuing collagen deposition. Using pharmacological interventions in pigs and mice undergoing CO we will interfere with specific activators of MMPs or collagen breakdown activities and quantify collagen type I transcription as well as the structure/function of the ischemic area and early scar. Aim 3. The structure and function of the mature (6 week) cardiac scar is dependent on the degree of early (< 48 h) degradation of collagen and to a lesser extent on their ensuing synthesis and crosslinking of collagen. Using pharmacological approaches to reduce MMP activity within the first 48 h after CO we propose that fibrosis and as a consequence overall fiber- and cross-fiber stiffness will be attenuated in the mature scar and that these events will be defined by the extent of early damage to the original collagen matrix. lschemic area and 6 week scar structure/function will be assessed as in aim 2.