High-Density Lipoproteins Retard the Progression of Atherosclerosis and Favorably Remodel Lesions Without Suppressing Indices of Inflammation or Oxidation

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Abstract
Objective— Protective properties of high-density lipoproteins (HDL) may include reverse cholesterol transport and suppression of oxidation and inflammation. These were investigated in vivo, as were the effects of HDL on the characteristics of atherosclerotic lesions. Methods and Results— Male apolipoprotein E knockout (apoE−/−) and apoE−/− mice expressing human apolipoprotein AI (hAI/apoE−/−) were studied up to 20 weeks after commencing a high-fat diet. Plasma HDL cholesterol was twice as high in hAI/apoE−/− mice. Over time, aortic root lesion area remained less in hAI/apoE−/− mice, although plaques became complex. In advanced lesions, plaque lipid was higher in apoE−/− mice, whereas plaque collagen and alpha actin were increased in hAI/apoE−/− mice. In nonlesional aorta, mRNA abundance for pro-inflammatory proteins (vascular cell adhesion molecule [VCAM]-1, intercellular adhesion molecule-1 [ICAM-1], monocyte chemoattractant protein-1 [MCP-1]) increased between 4 and 16 weeks in apoE−/− (but not wild-type) mice, and were not reduced by elevated HDL. Autoantibodies to malondialdehyde low-density lipoprotein (LDL) increased progressively in apoE−/− mice, with similar results in hAI/apoE−/− mice. Conclusions— HDL retarded plaque size progression despite greatly elevated plasma cholesterol. This effect was over a wide range of lesion severity. Expression of hAI reduced plaque lipid and increased the proportion of plaque occupied by collagen and smooth muscle cells, but did not affect indicators of inflammation or LDL oxidation. We have studied the progression of atherosclerosis in male apoE−/− and hAI/apoE−/− mice fed a Western diet. Elevation of HDL retarded the size progression of atherosclerosis, reduced plaque lipid content, and increased plaque collagen, despite greatly elevated non-HDL cholesterol. These changes occurred without evidence of reduced aortic inflammation or LDL oxidation.