REGULATION OF MACROPHAGE PLASMINOGEN ACTIVATION AND VASCULAR REMODELING

巨噬细胞纤溶酶原激活和血管重塑的调节

• 批准号: 6302472
• 负责人: DOMENICK J FALCONE
• 金额: $ 16.59万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302472
• 关键词: angiogenesis; angiostatins; annexins; apolipoprotein E; atherosclerotic plaque; extracellular matrix; extracellular matrix proteins; gene targeting; growth inhibitors; laboratory mouse; metalloendopeptidases; plasmin; plasminogen; plasminogen activator; protein sequence; proteolysis; receptor expression

The expression of matrix degrading enzymes by macrophages and macrophage-derived foam cells in atherosclerotic lesions has been proposed as a mechanism for the release of matrixbound growth factors and plaque destabilization. In this regard, macrophage plasminogen activation plays a central role in extracellular matrix degradation. Plasmin degrades several components of the extracellular matrix and activates a family of matrix-degrading metallo-proteinases. Macrophages localize and regulate plasminogen activation by their expression of a receptor for urokinase-type plasminogen activator (uPA) and several receptors for plasmin (ogen). The identities and regulation of these plasminogen receptors are not completely understood. In preliminary studies, we have demonstrated that annexin II is a constitutive plasmin receptor on murine macrophages and human monocyte-derived macrophages. In addition, we have demonstrated that autoproteolysis of membrane-bound plasmin is another mechanism by which pericellular plasmin is regulated. Following its activation, membrane-bound plasmin is proteolyzed into fragments with disparate physiologic properties. Partial NH2- terminal sequence of an enzymatically inactive 48 kDa plamin fragment, found in macrophage conditioned media and bound to cells, indicates that it comprises the entire sequence of angiostatin, a recently described inhibitor of endothelial cell proliferation and angiogenesis. The overall aims of studies proposed in this application are to: determine the regulation of pericellular proteolysis of plasmin and its consequences on macrophage function; determine whether proteolysis of membrane-bound plasmin generates fragments of plasmin expressing angiostatin activity; characterize macrophage and foam cell plasminogen receptors; and correlate aortic uPA and uPA receptor expression with lesion development in apoE-deficient mice. Result of these studies will help to elucidate the mechanisms by which macrophages orchestrate tissue remodeling and may provide us with novel interventional strategies for the treatment of atherosclerosis.

巨噬细胞和基质降解酶的表达 动脉粥样硬化病变中巨噬细胞衍生的泡沫细胞 提议作为释放基质束缚生长的机制 因素和斑块不稳定。 对此，巨噬细胞 纤溶酶原激活在细胞外基质中起着核心作用 降解。 纤溶酶可降解多种成分 细胞外基质并激活一系列基质降解 金属蛋白酶。 巨噬细胞定位和调节 通过表达受体来激活纤溶酶原 尿激酶型纤溶酶原激活剂 (uPA) 和几种受体 对于纤溶酶（原）。 这些机构的身份和监管 纤溶酶原受体尚未完全了解。 在 初步研究表明，annexin II 是一种 鼠巨噬细胞和人巨噬细胞上的组成型纤溶酶受体 单核细胞来源的巨噬细胞。 此外，我们还展示了 膜结合纤溶酶的自蛋白水解是另一种 细胞周纤溶酶的调节机制。 下列的 它的激活，膜结合纤溶酶被蛋白水解成 具有不同生理特性的片段。 部分NH2- 无酶活性的 48 kDa 纤溶酶蛋白的末端序列 片段，在巨噬细胞条件培养基中发现并结合 细胞，表明它包含血管抑制素的完整序列， 最近描述的内皮细胞增殖抑制剂 血管生成。 本研究提出的总体目标 应用目的： 确定细胞周的调节 纤溶酶的蛋白水解及其对巨噬细胞的影响 功能;确定膜结合蛋白是否水解 纤溶酶产生表达血管抑制素的纤溶酶片段 活动;表征巨噬细胞和泡沫细胞纤溶酶原 受体；并将主动脉 uPA 和 uPA 受体表达相关联 apoE 缺陷小鼠的病变发展。 这些结果 研究将有助于阐明巨噬细胞的机制 协调组织重塑并可能为我们提供新的 治疗动脉粥样硬化的介入策略。