Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering
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ORIGINAL CONTRIBUTION
Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering Carmen Härdtner1 · Jan Kornemann1 · Katja Krebs1 · Carolin A. Ehlert1 · Alina Jander1 · Jiadai Zou1 · Christopher Starz1 · Simon Rauterberg1 · Diana Sharipova1 · Bianca Dufner1 · Natalie Hoppe1 · Tsai‑Sang Dederichs1 · Florian Willecke1 · Peter Stachon1 · Timo Heidt1 · Dennis Wolf1 · Constantin von zur Mühlen1 · Josef Madl2 · Peter Kohl2 · Rafael Kaeser3 · Tobias Boettler3 · Elsbeth J. Pieterman4 · Hans M. G. Princen4 · Benoît Ho‑Tin‑Noé5 · Filip K. Swirski6 · Clinton S. Robbins7 · Christoph Bode1 · Andreas Zirlik1,8 · Ingo Hilgendorf1 Received: 6 September 2020 / Accepted: 1 December 2020 © The Author(s) 2020
Abstract Statins induce plaque regression characterized by reduced macrophage content in humans, but the underlying mechanisms remain speculative. Studying the translational APOE*3-Leiden.CETP mouse model with a humanized lipoprotein metabolism, we find that systemic cholesterol lowering by oral atorvastatin or dietary restriction inhibits monocyte infiltration, and reverses macrophage accumulation in atherosclerotic plaques. Contrary to current believes, none of (1) reduced monocyte influx (studied by cell fate mapping in thorax-shielded irradiation bone marrow chimeras), (2) enhanced macrophage egress (studied by fluorescent bead labeling and transfer), or (3) atorvastatin accumulation in murine or human plaque (assessed by mass spectrometry) could adequately account for the observed loss in macrophage content in plaques that undergo phenotypic regression. Instead, suppression of local proliferation of macrophages dominates phenotypic plaque regression in response to cholesterol lowering: the lower the levels of serum LDL-cholesterol and lipid contents in murine aortic and human carotid artery plaques, the lower the rates of in situ macrophage proliferation. Our study identifies macrophage proliferation as the predominant turnover determinant and an attractive target for inducing plaque regression. Keywords Atherosclerosis · Macrophage · Proliferation · Plaque regression
Introduction Carmen Härdtner and Jan Kornemann contributed equally. Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s0039 5-020-00838-4. * Ingo Hilgendorf ingo.hilgendorf@universitaets‑herzzentrum.de 1
Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106 Freiburg, Germany
Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, Freiburg, Germany
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Department of Medicine II, Faculty of Medicine, Medical Center–University Freiburg, University of Freiburg, Freiburg, Germany
International guidelines recommend treating patients with atherosclerotic disease with high-dose statins [20, 41]. For every 40 mg/dL reduction in low-cholesterol
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