Due to atherosclerosis is asymptomatic nature, it is difficult to investigate the progression of this disease in humans. Animals, especially mice with select genetic alterations, are very useful to investigate this disease. Mice with a double deficiency of LDLr and Apobec1 (Ldlr^-/-/Apobec1^-/-) show high levels of plasma total cholesterol on a normal chow diet, most of which is distributed in the LDL fraction. Consequently, spontaneous atherosclerotic plaques form in the aorta, a situation that is similar to human familial hypercholesterolemia.
We have revealed the important role of thecoagulation and fibrinolytic system in atherosclerosis. In this study, we examined the role of plasminogen in atherosclerosis with Ldlr^-/-/Apobec1^-/-mice.
We established Ldlr^-/-/Apobec1^-/-/Plasminogen^-/-(Ldlr^-/-/Apobec1^-/-/Plg^-/-) triple deficient mice from Ldlr^-/-/Apobec1^-/-mice and Plg^-/-mice. We have found that total cholesterol levels were significantly higher in Ldlr^-/-/Apobec1^-/-/Plg^-/-mice than in Ldlr^-/-/Apobec1^-/-mice. Almost all of the cholesterol accumulated in the LDL fraction, and the HDL cholesterol level was not different between both groups. However, Ldlr^-/-/Apobec1^-/-/Plg^-/-mice showed much smaller plaques in the aortic sinus. Furthermore, the migration of macrophages was suppressed by a plasminogen deficiency. Plasmin, the activator of plasminogen, promoted OxLDL uptake of macrophages. On the other hands, plasminogen didn't affect the expression of various scavenger receptors in macrophage. These results suggest that theactivation of plasminogen and the interaction plasminogen and OxLDL promote atherosclerosis in type lla familial hypercholesterolemia.