Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering
Standard
Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering. / Härdtner, Carmen; Kornemann, Jan; Krebs, Katja; Ehlert, Carolin A; Jander, Alina; Zou, Jiadai; Starz, Christopher; Rauterberg, Simon; Sharipova, Diana; Dufner, Bianca; Hoppe, Natalie; Dederichs, Tsai-Sang; Willecke, Florian; Stachon, Peter; Heidt, Timo; Wolf, Dennis; von Zur Mühlen, Constantin; Madl, Josef; Kohl, Peter; Kaeser, Rafael; Boettler, Tobias; Pieterman, Elsbeth J; Princen, Hans M G; Ho-Tin-Noé, Benoît; Swirski, Filip K; Robbins, Clinton S; Bode, Christoph; Zirlik, Andreas; Hilgendorf, Ingo.
in: BASIC RES CARDIOL, Jahrgang 115, Nr. 6, 09.12.2020, S. 78.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering
AU - Härdtner, Carmen
AU - Kornemann, Jan
AU - Krebs, Katja
AU - Ehlert, Carolin A
AU - Jander, Alina
AU - Zou, Jiadai
AU - Starz, Christopher
AU - Rauterberg, Simon
AU - Sharipova, Diana
AU - Dufner, Bianca
AU - Hoppe, Natalie
AU - Dederichs, Tsai-Sang
AU - Willecke, Florian
AU - Stachon, Peter
AU - Heidt, Timo
AU - Wolf, Dennis
AU - von Zur Mühlen, Constantin
AU - Madl, Josef
AU - Kohl, Peter
AU - Kaeser, Rafael
AU - Boettler, Tobias
AU - Pieterman, Elsbeth J
AU - Princen, Hans M G
AU - Ho-Tin-Noé, Benoît
AU - Swirski, Filip K
AU - Robbins, Clinton S
AU - Bode, Christoph
AU - Zirlik, Andreas
AU - Hilgendorf, Ingo
PY - 2020/12/9
Y1 - 2020/12/9
N2 - 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.
AB - 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.
U2 - 10.1007/s00395-020-00838-4
DO - 10.1007/s00395-020-00838-4
M3 - SCORING: Journal article
C2 - 33296022
VL - 115
SP - 78
JO - BASIC RES CARDIOL
JF - BASIC RES CARDIOL
SN - 0300-8428
IS - 6
ER -