Role of Tissue Factor in Atherosclerosis

动脉粥样硬化是一种复杂的进行性炎症性疾病，其特征是 巨噬细胞和淋巴细胞聚集，血管平滑肌细胞增殖和 动脉壁内脂质沉积。组织因子(Tf)是血管紧张素转换酶的主要细胞启动因子。 凝固性蛋白水解酶级联。Tf：FVII复合体激活FX和FXI导致凝血酶 产生、纤维蛋白沉积和血小板活化。此外，Tf：FVIla复合体是 促炎，部分是通过产生凝血酶，通过切割血管细胞来激活血管细胞 蛋白水解酶激活受体1(PAR-1)。在这项提案中，我们将使用遗传学和药理学 阐明转铁蛋白和PAR-1在动脉粥样硬化形成中作用的途径。我们将使用易患动脉粥样硬化的小鼠LDLR-/-和ApoE-/-来确定降低总转铁蛋白表达对动脉粥样硬化的影响。我们将通过用低Tf或Tf缺失小鼠的骨髓重建LDLR-/-小鼠的骨髓来研究巨噬细胞Tf在动脉粥样硬化中的作用。我们将使用一种有效的抗人转铁蛋白抗体来抑制人源化转铁蛋白小鼠的转铁蛋白活性。我们将产生高水平的转铁蛋白，这可能会增加血栓形成能力，并改变病变的表型。PAR-1在动脉粥样硬化中的作用将通过将PAR-1-/-小鼠与ApoE-/-小鼠杂交来分析。最后，我们将分析增加或减少TF表达或取消PAR-1表达对动脉粥样硬化病变小鼠动脉中促动脉粥样硬化基因IL-6、MCP-1和Gro-α表达的影响。这些综合研究将阐明转铁蛋白在动脉粥样硬化形成中的作用。这一信息可能提供重要的科学数据，可能导致新型抗转铁蛋白药物在动脉粥样硬化的临床治疗中的使用。

Atherosclerosis is a complex and progressive inflammatory disease characterized by an accumulation of macrophages and lymphocytes, vascular smooth muscle cell proliferation and deposition of lipids in the arterial wail. Tissue factor (TF) is the primary cellular initiator of the coagulation protease cascades. The TF:FVII complex activates FX and FXI leading to thrombin generation, fibrin deposition and platelet activation. In addition, the TF:FVIla complex is proinflammatory, in part, by generating thrombin that activates vascular cells by cleavage of protease activated receptor 1 (PAR-1). In this proposal, we will use genetic and pharmacological approaches to elucidate the roles of TF and PAR-1 in atherogenesis. We will determine the effects of reducing total TF expression on atherosclerosis using the atherosclerosis-prone mice LDLR-/- and ApoE-/-. We will examine the role of macrophage TF on atherosclerosis by reconstituting the bone marrow of LDLR-/- mice with bone marrow from either low TF or TF null mice. We will use a potent anti-human TF antibody to inhibit TF activity in mice humanized for TF. We will generate mice with high levels of TF, which may increase the thrombogenicity and change the phenotype of the lesions. The role of PAR-1 in atherosclerosis will be analyzed by crossing PAR-1-/- mice with ApoE-/- mice. Finally, we will analyze the effects of increasing or decreasing TF expression or abolishing PAR-1 expression on the expression of pro-atherogenic genes, such as IL-6, MCP-1 and Gro-alpha, in the aortas of mice with atherosclerotic lesions. These comprehensive studies will elucidate the role of TF in atherogenesis. This information may provide important scientific data that may lead to the use of novel anti-TF drugs in the clinical treatment of atherosclerosis.