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.
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