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

被引：47

作者：

Haerdtner, Carmen ^{[1
,2
]}

Kornemann, Jan ^{[1
,2
]}

Krebs, Katja ^{[1
,2
]}

Ehlert, Carolin A. ^{[1
,2
]}

Jander, Alina ^{[1
,2
]}

Zou, Jiadai ^{[1
,2
]}

Starz, Christopher ^{[1
,2
]}

Rauterberg, Simon ^{[1
,2
]}

Sharipova, Diana ^{[1
,2
]}

Dufner, Bianca ^{[1
,2
]}

Hoppe, Natalie ^{[1
,2
]}

Dederichs, Tsai-Sang ^{[1
,2
]}

Willecke, Florian ^{[1
,2
]}

Stachon, Peter ^{[1
,2
]}

Heidt, Timo ^{[1
,2
]}

Wolf, Dennis ^{[1
,2
]}

von zur Muehlen, Constantin ^{[1
,2
]}

Madl, Josef ^{[2
,3
]}

Kohl, Peter ^{[2
,3
]}

Kaeser, Rafael ^{[4
]}

Boettler, Tobias ^{[4
]}

Pieterman, Elsbeth J. ^{[5
]}

Princen, Hans M. G. ^{[5
]}

Ho-Tin-Noe, Benoit ^{[6
,7
]}

Swirski, Filip K. ^{[8
,9
]}

Robbins, Clinton S. ^{[10
]}

Bode, Christoph ^{[1
,2
]}

Zirlik, Andreas ^{[1
,2
,11
]}

Hilgendorf, Ingo ^{[1
,2
]}

机构：

[1] Univ Freiburg, Univ Heart Ctr Freiburg Bad Krozingen, Dept Cardiol & Angiol 1, 55 Hugstetter St, D-79106 Freiburg, Germany

[2] Univ Freiburg, Fac Med, 55 Hugstetter St, D-79106 Freiburg, Germany

[3] Univ Freiburg, Univ Heart Ctr Freiburg Bad Krozingen, Inst Expt Cardiovasc Med, Freiburg, Germany

[4] Univ Freiburg, Fac Med, Dept Med 2, Med Ctr, Freiburg, Germany

[5] Netherlands Org Appl Sci Res TNO, Metab Hlth Res, Leiden, Netherlands

[6] Univ Paris Diderot, INSERM, Unit 1148, Paris, France

[7] Sorbonne Paris Cite, Lab Vasc Translat Sci, Paris, France

[8] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA

[9] Harvard Med Sch, Boston, MA 02115 USA

[10] Univ Hlth Network, Peter Munk Cardiac Ctr, Toronto, ON, Canada

[11] Graz Univ, Dept Cardiol, Graz, Austria

来源：

BASIC RESEARCH IN CARDIOLOGY | 2020年 / 115卷 / 06期

关键词：

Atherosclerosis; Macrophage; Proliferation; Plaque regression;

D O I：

10.1007/s00395-020-00838-4

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页数：19

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