FUNCTION OF MATRIX METALLOPROTEINASES AND HEPARIN

受控重塑是血管生长和血管再生的基本特征 发展以及对疾病的病理反应。虽然很多 血管生物学研究的焦点一直集中在 通过刺激平滑肌细胞的堆积来增加壁质量 和基质，我们认为控制萎缩和降解的因素 矩阵具有同等的重要性。这些因素可能是至关重要的 动脉粥样硬化斑块破裂和过度内膜的决定因素 血管重建后增厚。这样做的主要目标是 研究计划将检验两个假设：1.矩阵 金属蛋白酶(MMPs)是动脉平滑肌细胞所必需的 移行和增殖以及损伤和基质周转 2.肝素通过干扰SMC功能抑制SMC功能 与间质胶原酶的转录以及 其他可降解基质的蛋白酶。这些实验将定义 MMPs在体外大鼠SMC功能和损伤颈动脉中的作用 通过复制转导细胞的新药理学方法- 过度表达MMPs主要抑制物的有缺陷的逆转录病毒载体， 金属蛋白酶组织抑制因子-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研究 这种蛋白水解酶在动脉粥样硬化形成的猴子模型和在老年人中的表达 颈动脉斑块显示纤维帽破裂和出血。 平行实验将试图确定肝素在哪里起作用来控制 胶原酶转录(蛋白激酶C/AP-1途径)在恒河猴中的表达 大鼠在体外和体内的SMC；最初的焦点将是调节 MAPK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.