Early intermittent hyperlipidaemia alters tissue macrophages to fuel atherosclerosis

Minoru Takaoka, Xiaohui Zhao, Hwee Ying Lim, Costan G. Magnussen, Owen Ang, Nadine Suffee, Patricia R. Schrank, Wei Siong Ong, Dimitrios Tsiantoulas, Felix Sommer, Sarajo K. Mohanta, James Harrison, Yaxing Meng, Ludivine Laurans, Feitong Wu, Yuning Lu, Leanne Masters, Stephen A. Newland, Laura Denti, Mingyang Hong, Mouna Chajadine, Markus Juonala, Juhani S. Koskinen, Mika Kähönen, Katja Pahkala, Suvi P. Rovio, Juha Mykkänen, Russell Thomson, Tsuneyasu Kaisho, Andreas J. R. Habenicht, Marc Clement, Alain Tedgui, Hafid Ait-Oufella, Tian X. Zhao, Meritxell Nus, Christiana Ruhrberg, Soraya Taleb, Jesse W. Williams, Olli T. Raitakari, Véronique Angeli and Ziad Mallat ()
Additional contact information
Minoru Takaoka: Heart and Lung Research Institute
Xiaohui Zhao: Heart and Lung Research Institute
Hwee Ying Lim: National University of Singapore
Costan G. Magnussen: Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku
Owen Ang: National University of Singapore
Nadine Suffee: PARCC
Patricia R. Schrank: University of Minnesota
Wei Siong Ong: National University of Singapore
Dimitrios Tsiantoulas: Heart and Lung Research Institute
Felix Sommer: University of Kiel and University Hospital Schleswig Holstein (UKSH)
Sarajo K. Mohanta: Ludwig-Maximilians-Universität München (LMU)
James Harrison: Heart and Lung Research Institute
Yaxing Meng: Baker Heart and Diabetes Institute
Ludivine Laurans: PARCC
Feitong Wu: Baker Heart and Diabetes Institute
Yuning Lu: Heart and Lung Research Institute
Leanne Masters: Heart and Lung Research Institute
Stephen A. Newland: Heart and Lung Research Institute
Laura Denti: University College London
Mingyang Hong: Ludwig-Maximilians-Universität München (LMU)
Mouna Chajadine: PARCC
Markus Juonala: University of Turku
Juhani S. Koskinen: Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku
Mika Kähönen: University of Tampere
Katja Pahkala: Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku
Suvi P. Rovio: Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku
Juha Mykkänen: Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku
Russell Thomson: Baker Heart and Diabetes Institute
Tsuneyasu Kaisho: Wakayama Medical University
Andreas J. R. Habenicht: Ludwig-Maximilians-Universität München (LMU)
Marc Clement: Heart and Lung Research Institute
Alain Tedgui: PARCC
Hafid Ait-Oufella: PARCC
Tian X. Zhao: Heart and Lung Research Institute
Meritxell Nus: Heart and Lung Research Institute
Christiana Ruhrberg: University College London
Soraya Taleb: PARCC
Jesse W. Williams: University of Minnesota
Olli T. Raitakari: Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku
Véronique Angeli: National University of Singapore
Ziad Mallat: Heart and Lung Research Institute

Nature, 2024, vol. 634, issue 8033, 457-465

Abstract: Abstract Hyperlipidaemia is a major risk factor of atherosclerotic cardiovascular disease (ASCVD). Risk of cardiovascular events depends on cumulative lifetime exposure to low-density lipoprotein cholesterol (LDL-C) and, independently, on the time course of exposure to LDL-C, with early exposure being associated with a higher risk1. Furthermore, LDL-C fluctuations are associated with ASCVD outcomes2–4. However, the precise mechanisms behind this increased ASCVD risk are not understood. Here we find that early intermittent feeding of mice on a high-cholesterol Western-type diet (WD) accelerates atherosclerosis compared with late continuous exposure to the WD, despite similar cumulative circulating LDL-C levels. We find that early intermittent hyperlipidaemia alters the number and homeostatic phenotype of resident-like arterial macrophages. Macrophage genes with altered expression are enriched for genes linked to human ASCVD in genome-wide association studies. We show that LYVE1+ resident macrophages are atheroprotective, and identify biological pathways related to actin filament organization, of which alteration accelerates atherosclerosis. Using the Young Finns Study, we show that exposure to cholesterol early in life is significantly associated with the incidence and size of carotid atherosclerotic plaques in mid-adulthood. In summary, our results identify early intermittent exposure to cholesterol as a strong determinant of accelerated atherosclerosis, highlighting the importance of optimal control of hyperlipidaemia early in life, and providing insights into the underlying biological mechanisms. This knowledge will be essential to designing effective therapeutic strategies to combat ASCVD.

Date: 2024
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DOI: 10.1038/s41586-024-07993-x

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