Murine bone marrow transplantation as a novel approach to studying the role of macrophages in lipoprotein metabolism and atherogenesis.

In recent years, the development of transgenic and gene targeting technologies have made the mouse a powerful model to dissect the contribution of various genes to lipoprotein metabolism and atherosclerosis susceptibility. Here, murine bone marrow transplantation (BMT) is presented as a method to investigate the role of the macrophage in lipoprotein metabolism and atherosclerosis. This approach has been successfully implemented in apolipoprotein (apo) E-deficient mice, which develop severe hyperlipidemia and extensive aortic and coronary atherosclerosis. BMT was performed as a way to deliver macrophages with the normal complement of the apoE gene to the apoE-deficient mice. BMT resulted in the appearance of apoE in plasma, in a sustained drop in cholesterol levels, and in the normalization of the lipoprotein profile. In addition, BMT protected the apoE-deficient mice from diet-induced hypercholesterolemia and atherosclerosis. These data demonstrate that extrahepatic apoE secreted into the plasma compartment is functionally active and promotes lipoprotein clearance, and establish BMT as a novel approach to dissecting the role of macrophages in atherosclerosis and lipid metabolism. In addition, these findings show that the liver is not the obligatory target organ in gene therapy of dyslipidemia, and suggest the use of the macrophage as a vehicle.