HDL is essential for atherosclerotic lesion regression in Apoe knockout mice by bone marrow Apoe reconstitution. (November 2018)

• Record Type: Journal Article
• Authors: van der Sluis, Ronald J.; Verwilligen, Robin A.F.; Lendvai, Zsuzsanna; Wever, Robbert; Hoekstra, Menno; Van Eck, Miranda
• Is Part Of: Atherosclerosis. Volume 278(2018)
• Page Start: 240
• Page End: 249
• Publication Date: 2018-11
• Subjects: Atherosclerosis -- Cholesterol -- HDL -- Regression; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2018.09.038
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: Although studies in mice have suggested that lesion regression is feasible, the underlying mechanisms remain largely unknown. Here we determined the impact of high-density lipoprotein (HDL) on atherosclerosis regression outcome. Methods: Atherosclerotic lesion dynamics were studied upon bone marrow transplantation-mediated re-introduction of apolipoprotein E ( Apoe ) in Apoe knockout mice. Probucol was used to pharmacologically deplete HDL. Results: Restoration of Apoe function was associated with an initial growth of atherosclerotic lesions and parallel decrease in lesional macrophage foam cell content (47 ± 4% at 4 weeks versus 72 ± 2% at baseline: p < 0.001), despite the fact that cholesterol levels were markedly reduced. Notably, significant lesion regression was detected from 4 weeks onwards, when plasma cholesterol levels had returned to the normolipidemic range. As a result, lesions were 41% smaller ( p < 0.05) at 8 weeks than at 4 weeks after bone marrow transplantation. Regressed lesions contained an even lower level of macrophage foam cells (33 ± 5%: p < 0.001) and were rich in collagen. Probucol co-treatment was associated with a 3.2-fold lower ( p < 0.05) plasma HDL-cholesterol level and a more pro-inflammatory (CCR2+) monocyte phenotype. Importantly, probucol-treated mice exhibited atherosclerotic lesions that were larger than those of regular chow diet-fed bone marrow transplanted mice at 8 weeks (186 ± 15*10 3 μm 2 for probucol-treated versus 120 ± 19*10 3 μm 2 for controls: p < 0.05). Conclusions: We have shown that probucol-induced HDL deficiency impairs the ability of established lesions to regress in response to reversal of the genetic hypercholesterolemia in Apoe knockout mice. Our studies thus highlight a crucial role for HDL in the process of atherosclerosis regression. Highlights: Reversal of hypercholesterolemia reduces lesional foam cell content in Apoe KO mice. Normalization of cholesterol levels induces lesion regression in Apoe KO mice. Probucol treatment is associated with a more pro-inflammatory monocyte phenotype. Probucol-induced HDL lowering impairs the ability of established lesions to regress.