Stage-Specific Remodeling of Atherosclerotic Lesions upon Cholesterol Lowering in LDL Receptor Knockout Mice

Abstract

Reducing the concentration of circulating lipids leads to decreased cardiovascular morbidity and mortality, but the dynamic remodeling that established atherosclerotic lesions undergo upon lipid lowering is poorly understood. Early or advanced lesions in the aortic root were induced by feeding LDL receptor knockout mice a high-fat, high-cholesterol Western-type diet for 5 or 9 weeks, respectively. In the first week after switching to a chow diet, plasma total cholesterol levels dropped 70%, but both early and advanced lesions increased in size. Early lesions grew because of an increase in smooth muscle cells; advanced lesions had an enlargement of absolute macrophage area. From 1 to 3 weeks after the diet switch, plasma total cholesterol levels were completely normalized, but the size of early lesions remained stable; however, advanced lesions became smaller due to a reduction of the absolute macrophage area. From 3 to 6 weeks, both early and advanced lesions progressed further, as a result of expansion of the absolute collagen and necrotic core area. In contrast, early lesions became proinflammatory, as evidenced by the increased infiltration of neutrophils and increased oxidative stress, probably caused by the activation of mast cells in the adventitia. Thus, the severity of atherosclerotic lesions affects their dynamic response to lipid lowering, indicating the importance of establishing stage-specific therapeutic protocols for the treatment of atherosclerosis.