REGULATION OF MACROPHAGE PLASMINOGEN ACTIVATION AND VASCULAR REMODELING

巨噬细胞基质降解酶的表达及 巨噬细胞源性泡沫细胞在动脉粥样硬化病变中的作用 被认为是释放基质生长的机制， 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着重要作用 降解 纤维蛋白溶酶降解纤维蛋白的几种组分， 细胞外基质和激活一个家庭的基质降解 金属蛋白酶 宏观调控 纤溶酶原激活通过其受体的表达， 尿激酶型纤溶酶原激活物（uPA）和几种受体 对于纤溶酶（原）。 它们的身份和监管 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 单核细胞衍生的巨噬细胞。 此外，我们还证明了 膜结合纤溶酶自身蛋白水解是另一个 调节细胞周围纤溶酶的机制。 以下 它的活化，膜结合纤溶酶被蛋白水解成 具有不同生理特性的碎片。 部分NH 2- 无酶活性48 kDa纤溶蛋白的末端序列 片段，在巨噬细胞条件培养基中发现，并与 细胞，表明它包含血管抑素的整个序列， 最近描述的内皮细胞增殖抑制剂， 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 纤溶酶的蛋白水解及其对巨噬细胞的影响 功能;确定是否膜结合的蛋白水解 纤溶酶产生表达血管抑素的纤溶酶片段 活性;表征巨噬细胞和泡沫细胞纤溶酶原 主动脉uPA和uPA受体表达相关 与apoE缺陷小鼠的病变发展有关。 由于这些 研究将有助于阐明巨噬细胞 协调组织重塑，并可能为我们提供新的 动脉粥样硬化治疗的介入策略。

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.