FUNCTION OF MATRIX METALLOPROTEINASES AND HEPARIN

受控重塑是血管生长的基本特征， 发展以及对疾病的病理反应。虽然大部分 血管生物学研究的焦点一直是那些 通过刺激平滑肌细胞的积累增加壁质量 和基质，我们提出，控制萎缩和退化的因素， 矩阵同样重要。这些因素可能至关重要 动脉粥样硬化斑块破裂和内膜过度增生的决定因素 血管重建后增厚。这项工作的主要目的是 研究计划将测试两个假设：1。矩阵 金属蛋白酶（MMPs）是动脉平滑肌细胞 迁移和增殖以及基质周转， 动脉粥样硬化; 2.肝素通过干扰SMC的功能抑制SMC的功能 随着间质胶原酶的转录以及几种 其他基质降解蛋白酶。这些实验将确定 基质金属蛋白酶在大鼠颈动脉平滑肌细胞功能中的作用 用复制转导的细胞的新药理学方法- 过表达MMPs主要抑制剂的缺陷型逆转录病毒载体， 金属蛋白酶组织抑制剂-1。我们将尝试定义一个角色 间质胶原酶在动脉粥样硬化中的表达 这种蛋白酶在猴子动脉粥样硬化模型和先进的人类 显示纤维帽破裂和出血的颈动脉斑块。 平行实验将试图确定肝素在何处起控制作用 狒狒胶原酶转录（蛋白激酶C/AP-1途径）， 大鼠SMC在体外和体内;重点将首先放在调控 MAP激酶和Jun B的表达。

Controlled remodeling is an essential feature of blood vessel growth and development as well as the pathological response to disease. Although much of the focus of vascular biological research has been on factors that increase wall mass by stimulating the accumulation of smooth muscle cells and matrix, we propose that factors controlling atrophy and degradation of matrix are of equal importance. Such factors might be critical determinants of atherosclerotic plaque rupture and excessive intimal thickening after vascular reconstruction. The primary objective of this research program will be to test two hypotheses: 1. matrix metalloproteinases (MMPs) are required for arterial smooth muscle cell migration and proliferation as well as matrix turnover in injured and atherosclerotic arteries; 2. heparin inhibits SMC function by interfering with the transcription of interstitial collagenase as well as several other matrix-degrading proteases. The experiments will define the role of MMPs in rat SMC function in vitro and in injured carotid artery using a novel pharmacological approach with cells transduced with replication- defective retroviral vectors overexpressing the major inhibitor of MMPs, tissue inhibitor of metalloproteinase-1. We will attempt to define a role for interstitial collagenase in atherosclerosis by studying the expression of this protease in a monkey model of atherogenesis and in advanced human carotid artery plaques that exhibit fibrous cap disruption and hemorrhage. Parallel experiments will attempt to define where heparin acts to control collagenase transcription (protein kinase C/AP-1 pathway) in baboon and rat SMCs in vitro and in vivo; the focus will initially be on regulation of MAP kinase and Jun B expression.