Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice[S]
Atherosclerosis-related CVD causes nearly 20 million deaths annually. Most patients are treated after plaques develop, so therapies must regress existing lesions. Current therapies reduce plaque volume, but targeting all apoB-containing lipoproteins with intensive combinations that include alirocuma...
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doaj-ef5373475cbd46ad9e98e8368ae8f8d02021-04-29T04:38:52ZengElsevierJournal of Lipid Research0022-22752020-03-01613365375Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice[S]Marianne G. Pouwer0Elsbet J. Pieterman1Nicole Worms2Nanda Keijzer3J. Wouter Jukema4Jesper Gromada5Viktoria Gusarova6Hans M.G. Princen7Metabolic Health Research,The Netherlands Organization of Applied Scientific Research (TNO), Gaubius Laboratory, Leiden, The Netherlands; Department of CardiologyLeiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine,Leiden University Medical Center, Leiden, The NetherlandsMetabolic Health Research,The Netherlands Organization of Applied Scientific Research (TNO), Gaubius Laboratory, Leiden, The NetherlandsMetabolic Health Research,The Netherlands Organization of Applied Scientific Research (TNO), Gaubius Laboratory, Leiden, The NetherlandsMetabolic Health Research,The Netherlands Organization of Applied Scientific Research (TNO), Gaubius Laboratory, Leiden, The NetherlandsDepartment of CardiologyLeiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine,Leiden University Medical Center, Leiden, The NetherlandsRegeneron Pharmaceuticals, Tarrytown, NYTo whom correspondence should be addressed. (V.G.) viktoria.gusarova@regeneron.com; Regeneron Pharmaceuticals, Tarrytown, NY; To whom correspondence should be addressed. (H.M.G.P); hans.princen@tno.nlTo whom correspondence should be addressed. (H.M.G.P); hans.princen@tno.nl; Metabolic Health Research,The Netherlands Organization of Applied Scientific Research (TNO), Gaubius Laboratory, Leiden, The Netherlands; To whom correspondence should be addressed. (H.M.G.P); hans.princen@tno.nlAtherosclerosis-related CVD causes nearly 20 million deaths annually. Most patients are treated after plaques develop, so therapies must regress existing lesions. Current therapies reduce plaque volume, but targeting all apoB-containing lipoproteins with intensive combinations that include alirocumab or evinacumab, monoclonal antibodies against cholesterol-regulating proprotein convertase subtilisin/kexin type 9 and angiopoietin-like protein 3, may provide more benefit. We investigated the effect of such lipid-lowering interventions on atherosclerosis in APOE*3-Leiden.CETP mice, a well-established model for hyperlipidemia. Mice were fed a Western-type diet for 13 weeks and thereafter matched into a baseline group (euthanized at 13 weeks) and five groups that received diet alone (control) or with treatment [atorvastatin; atorvastatin and alirocumab; atorvastatin and evinacumab; or atorvastatin, alirocumab, and evinacumab (triple therapy)] for 25 weeks. We measured effects on cholesterol levels, plaque composition and morphology, monocyte adherence, and macrophage proliferation. All interventions reduced plasma total cholesterol (37% with atorvastatin to 80% with triple treatment; all P < 0.001). Triple treatment decreased non-HDL-C to 1.0 mmol/l (91% difference from control; P < 0.001). Atorvastatin reduced atherosclerosis progression by 28% versus control (P < 0.001); double treatment completely blocked progression and diminished lesion severity. Triple treatment regressed lesion size versus baseline in the thoracic aorta by 50% and the aortic root by 36% (both P < 0.05 vs. baseline), decreased macrophage accumulation through reduced proliferation, and abated lesion severity. Thus, high-intensive cholesterol-lowering triple treatment targeting all apoB-containing lipoproteins regresses atherosclerotic lesion area and improves lesion composition in mice, making it a promising potential approach for treating atherosclerosis.http://www.sciencedirect.com/science/article/pii/S0022227520435205atherosclerosisdrug therapy/hypolipidemic drugsmacrophages/monocytesapolipoproteinsantibodiesregression |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marianne G. Pouwer Elsbet J. Pieterman Nicole Worms Nanda Keijzer J. Wouter Jukema Jesper Gromada Viktoria Gusarova Hans M.G. Princen |
spellingShingle |
Marianne G. Pouwer Elsbet J. Pieterman Nicole Worms Nanda Keijzer J. Wouter Jukema Jesper Gromada Viktoria Gusarova Hans M.G. Princen Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice[S] Journal of Lipid Research atherosclerosis drug therapy/hypolipidemic drugs macrophages/monocytes apolipoproteins antibodies regression |
author_facet |
Marianne G. Pouwer Elsbet J. Pieterman Nicole Worms Nanda Keijzer J. Wouter Jukema Jesper Gromada Viktoria Gusarova Hans M.G. Princen |
author_sort |
Marianne G. Pouwer |
title |
Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice[S] |
title_short |
Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice[S] |
title_full |
Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice[S] |
title_fullStr |
Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice[S] |
title_full_unstemmed |
Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice[S] |
title_sort |
alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice[s] |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2020-03-01 |
description |
Atherosclerosis-related CVD causes nearly 20 million deaths annually. Most patients are treated after plaques develop, so therapies must regress existing lesions. Current therapies reduce plaque volume, but targeting all apoB-containing lipoproteins with intensive combinations that include alirocumab or evinacumab, monoclonal antibodies against cholesterol-regulating proprotein convertase subtilisin/kexin type 9 and angiopoietin-like protein 3, may provide more benefit. We investigated the effect of such lipid-lowering interventions on atherosclerosis in APOE*3-Leiden.CETP mice, a well-established model for hyperlipidemia. Mice were fed a Western-type diet for 13 weeks and thereafter matched into a baseline group (euthanized at 13 weeks) and five groups that received diet alone (control) or with treatment [atorvastatin; atorvastatin and alirocumab; atorvastatin and evinacumab; or atorvastatin, alirocumab, and evinacumab (triple therapy)] for 25 weeks. We measured effects on cholesterol levels, plaque composition and morphology, monocyte adherence, and macrophage proliferation. All interventions reduced plasma total cholesterol (37% with atorvastatin to 80% with triple treatment; all P < 0.001). Triple treatment decreased non-HDL-C to 1.0 mmol/l (91% difference from control; P < 0.001). Atorvastatin reduced atherosclerosis progression by 28% versus control (P < 0.001); double treatment completely blocked progression and diminished lesion severity. Triple treatment regressed lesion size versus baseline in the thoracic aorta by 50% and the aortic root by 36% (both P < 0.05 vs. baseline), decreased macrophage accumulation through reduced proliferation, and abated lesion severity. Thus, high-intensive cholesterol-lowering triple treatment targeting all apoB-containing lipoproteins regresses atherosclerotic lesion area and improves lesion composition in mice, making it a promising potential approach for treating atherosclerosis. |
topic |
atherosclerosis drug therapy/hypolipidemic drugs macrophages/monocytes apolipoproteins antibodies regression |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520435205 |
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