CHAPTER 8 Stage-specific remodelling of atherosclerotic lesions upon cholesterol lowering in LDL receptor knockout mice

Lipid lowering reduces cardiovascular morbidity and mortality. However, the dynamic remodeling of established atherosclerotic lesions upon lipid lowering is poorly understood. Early and advanced lesions in the aortic root were induced by feeding LDL receptor knockout mice a high fat/high cholesterol Western-type diet for 5 and 9 weeks, respectively. Lipid lowering was achieved by switching mice to chow diet. In the first week after the diet switch, plasma total cholesterol (TC) levels dropped 70%, but both early and advanced lesions increased in size. Early lesions grew due to an increase in smooth muscle cells while advanced lesions showed an enlargement of the absolute macrophage area. From 1 to 3 weeks, plasma TC levels were completely normalized. This did not influence the size of early lesions. 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, increased oxidative stress, probably caused by the activation of mast cells in the adventitia. In conclusion, the severity of the atherosclerotic lesion affects its dynamic response to lipid lowering, indicating the importance of establishing stage-specific therapeutic protocols for the treatment of atherosclerosis. --Am. J. Pathol. 2011; 179(3):1522-32---