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: 6442297
• 负责人: DOMENICK J FALCONE
• 金额: $ 28.07万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6442297
• 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.

巨噬细胞表达基质降解酶的研究进展 动脉粥样硬化病变中的巨噬细胞源性泡沫细胞 提出了一种释放基质结合生长的机制 因素和斑块不稳定。在这方面，巨噬细胞 纤溶酶原激活在细胞外基质中起核心作用 退化。纤溶酶可降解血管中的几种成分 细胞外基质，并激活一系列基质降解 金属蛋白酶。巨噬细胞的定位和调节 纤溶酶原通过其受体的表达而激活 尿激酶型纤溶酶原激活物及其几种受体 用于纤溶酶(原)。这些机构的身份和监管 纤溶酶原受体尚不完全清楚。在……里面 初步研究表明，膜联蛋白II是一种 小鼠巨噬细胞和人巨噬细胞上的结构性纤溶酶受体 单核细胞来源的巨噬细胞。此外，我们还展示了 膜结合的纤溶酶的自蛋白分解是另一个 调节细胞周型纤溶酶的机制。跟随 它的激活，结合在膜上的纤溶酶被蛋白质分解成 具有不同生理特性的碎片。部分氨水- 一个酶失活的48 kDa模板的末端序列 片段，在巨噬细胞条件培养液中发现并结合到 细胞，表明它包含血管抑素的整个序列， 一种新近发现的内皮细胞增殖和抑制因子 血管生成。本报告中提出的研究的总体目标 应用是：确定细胞周围的调节 纤溶酶的蛋白分解及其对巨噬细胞的影响 功能；确定膜结合的蛋白降解是否 纤溶酶产生表达血管抑素的纤溶酶片段 活性；巨噬细胞和泡沫细胞纤溶酶原特性 受体；并与主动脉uPA和uPA受体表达相关 与载脂蛋白E缺陷小鼠的病变发展有关。这一切的结果 研究将有助于阐明巨噬细胞 协调组织重塑，可能为我们提供新的 动脉粥样硬化的介入治疗策略。