Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering.

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.

• Authors: Carmen Härdtner, Jan Kornemann, Katja Krebs, Carolin A Ehlert, Alina Jander, Jiadai Zou, Christopher Starz, Simon Rauterberg, Diana Sharipova, Bianca Dufner, Natalie Hoppe, Tsai-Sang Dederichs, Florian Willecke, Peter Stachon, Timo Heidt, Dennis Wolf, Constantin von Zur Mühlen, Josef Madl, Peter Kohl, Rafael Kaeser, Tobias Boettler, Elsbeth J Pieterman, Hans M G Princen, Benoît Ho-Tin-Noé, Filip K Swirski, Clinton S Robbins, Christoph Bode, Andreas Zirlik, Ingo Hilgendorf
• Journal: Basic research in cardiology (Basic Res Cardiol) Vol. 115 Issue 6 Pg. 78 (12 09 2020) ISSN: 1435-1803 [Electronic] Germany
• PMID: 33296022 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoprotein E3
• Biomarkers
• Cholesterol Ester Transfer Proteins
• Cholesterol, LDL
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Receptors, LDL
• Atorvastatin

Topics

• Animals
• Apolipoprotein E3 (genetics)
• Atherosclerosis (genetics, metabolism, pathology, therapy)
• Atorvastatin (pharmacology)
• Biomarkers (blood)
• Cell Proliferation (drug effects)
• Cholesterol Ester Transfer Proteins (genetics)
• Cholesterol, LDL (blood)
• Diet, Fat-Restricted
• Disease Models, Animal
• Down-Regulation
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Macrophages (drug effects, metabolism, pathology)
• Mice, Inbred C57BL
• Mice, Knockout, ApoE
• Plaque, Atherosclerotic
• Receptors, LDL (genetics)