Top

Published in:

01-12-2020 | Atorvastatin | Original Contribution

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

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

Published in: Basic Research in Cardiology | Issue 6/2020

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.

Available only for authorised users

Albarrán-Juárez J, Kaur H, Grimm M, Offermanns S, Wettschureck N (2016) Lineage tracing of cells involved in atherosclerosis. Atherosclerosis 251:445–453. https://doi.org/10.1016/j.atherosclerosis.2016.06.012CrossRefPubMed

Babelova A, Sedding DG, Brandes RP (2013) Anti-atherosclerotic mechanisms of statin therapy. Curr Opin Pharmacol 13:260–264. https://doi.org/10.1016/j.coph.2013.01.004CrossRefPubMed

Bea F, Blessing E, Bennett B, Levitz M, Wallace EP, Rosenfeld ME (2002) Simvastatin promotes atherosclerotic plaque stability in apoE-deficient mice independently of lipid lowering. Arterioscler Thromb Vasc Biol 22:1832–1837. https://doi.org/10.1161/01.ATV.0000036081.01231.16CrossRefPubMed

Boada C, Zinger A, Tsao C, Zhao P, Martinez JO, Hartman K, Naoi T, Sukhoveshin R, Sushnitha M, Molinaro R, Trachtenberg B, Cooke JP, Tasciotti E (2020) Rapamycin-loaded biomimetic nanoparticles reverse vascular inflammation. Circ Res 126:25–37. https://doi.org/10.1161/CIRCRESAHA.119.315185CrossRefPubMed

Bonetti PO, Lerman LO, Napoli C, Lerman A (2003) Statin effects beyond lipid lowering—are they clinically relevant. Eur Heart J 24:225–248. https://doi.org/10.1016/S0195-668X0200419-0CrossRefPubMed

Bot I, Jukema JW, Lankhuizen IM, van Berkel TJ, Biessen EA (2011) Atorvastatin inhibits plaque development and adventitial neovascularization in ApoE deficient mice independent of plasma cholesterol levels. Atherosclerosis 214:295–300. https://doi.org/10.1016/j.atherosclerosis.2010.11.008CrossRefPubMed

Bulgarelli A, Leite ACJ, Dias AA, Maranhao RC (2013) Anti-atherogenic effects of methotrexate carried by a lipid nanoemulsion that binds to LDL receptors in cholesterol-fed rabbits. Cardiovasc Drugs Ther 27:531–539. https://doi.org/10.1007/s10557-013-6488-3CrossRefPubMed

Chan ES, Cronstein BN (2010) Methotrexate–how does it really work. Nat Rev Rheumatol 6:175–178. https://doi.org/10.1038/nrrheum.2010.5CrossRefPubMed

Chappell J, Harman JL, Narasimhan VM, Yu H, Foote K, Simons BD, Bennett MR, Jørgensen HF (2016) Extensive proliferation of a subset of differentiated, yet plastic, medial vascular smooth muscle cells contributes to neointimal formation in mouse injury and atherosclerosis models. Circ Res 119:1313–1323. https://doi.org/10.1161/CIRCRESAHA.116.309799CrossRefPubMedPubMedCentral

10.

Chen Z, Fukutomi T, Zago AC, Ehlers R, Detmers PA, Wright SD, Rogers C, Simon DI (2002) Simvastatin reduces neointimal thickening in low-density lipoprotein receptor-deficient mice after experimental angioplasty without changing plasma lipids. Circulation 106:20–23. https://doi.org/10.1161/01.CIR.0000022843.76104.01CrossRefPubMed

11.

Lima D, A, Hua N, C Maranhao R, A Hamilton J, (2017) Evaluation of atherosclerotic lesions in cholesterol-fed mice during treatment with paclitaxel in lipid nanoparticles: a magnetic resonance imaging study. J Biomed Res 31:116–121. https://doi.org/10.7555/JBR.31.20160123CrossRefPubMedCentral

12.

Depuydt MA, Prange KH, Slenders L, Örd T, Elbersen D, Boltjes A, de Jager SC, Asselbergs FW, de Borst GJ, Aavik E, Lönnberg T, Lutgens E, Glass CK, den Ruijter HM, Kaikkonen MU, Bot I, Slütter B, van der Laan SW, Yla-Herttuala S, Mokry M, Kuiper J, de Winther MP, Pasterkamp G (2020) Microanatomy of the human atherosclerotic plaque by single-cell transcriptomics. Circ Res. https://doi.org/10.1161/CIRCRESAHA.120.316770CrossRefPubMedPubMedCentral

13.

Distel E, Barrett TJ, Chung K, Girgis NM, Parathath S, Essau CC, Murphy AJ, Moore KJ, Fisher EA (2014) miR33 inhibition overcomes deleterious effects of diabetes mellitus on atherosclerosis plaque regression in mice. Circ Res 115:759–769. https://doi.org/10.1161/CIRCRESAHA.115.304164CrossRefPubMedPubMedCentral

14.

Duivenvoorden R, Tang J, Cormode DP, Mieszawska AJ, Izquierdo-Garcia D, Ozcan C, Otten MJ, Zaidi N, Lobatto ME, van Rijs SM, Priem B, Kuan EL, Martel C, Hewing B, Sager H, Nahrendorf M, Randolph GJ, Stroes ES, Fuster V, Fisher EA, Fayad ZA, Mulder WJ (2014) A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation. Nat Commun 5:3065. https://doi.org/10.1038/ncomms4065CrossRefPubMed

15.

Ensan S, Li A, Besla R, Degousee N, Cosme J, Roufaiel M, Shikatani EA, El-Maklizi M, Williams JW, Robins L, Li C, Lewis B, Yun TJ, Lee JS, Wieghofer P, Khattar R, Farrokhi K, Byrne J, Ouzounian M, Zavitz CC, Levy GA, Bauer CM, Libby P, Husain M, Swirski FK, Cheong C, Prinz M, Hilgendorf I, Randolph GJ, Epelman S, Gramolini AO, Cybulsky MI, Rubin BB, Robbins CS (2016) Self-renewing resident arterial macrophages arise from embryonic CX3CR1(+) precursors and circulating monocytes immediately after birth. Nat Immunol 17:159–168. https://doi.org/10.1038/ni.3343CrossRefPubMed

16.

Feig JE, Parathath S, Rong JX, Mick SL, Vengrenyuk Y, Grauer L, Young SG, Fisher EA (2011) Reversal of hyperlipidemia with a genetic switch favorably affects the content and inflammatory state of macrophages in atherosclerotic plaques. Circulation 123:989–998. https://doi.org/10.1161/CIRCULATIONAHA.110.984146CrossRefPubMedPubMedCentral

17.

Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, Hegele RA, Krauss RM, Raal FJ, Schunkert H, Watts GF, Boren J, Fazio S, Horton JD, Masana L, Nicholls SJ, Nordestgaard BG, van de Sluis B, Taskinen MR, Tokgozoglu L, Landmesser U, Laufs U, Wiklund O, Stock JK, Chapman MJ, Catapano AL (2017) Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 38:2459–2472. https://doi.org/10.1093/eurheartj/ehx144CrossRefPubMedPubMedCentral

18.

Fernandez DM, Rahman AH, Fernandez NF, Chudnovskiy A, Amir ED, Amadori L, Khan NS, Wong CK, Shamailova R, Hill CA, Wang Z, Remark R, Li JR, Pina C, Faries C, Awad AJ, Moss N, Bjorkegren JLM, Kim-Schulze S, Gnjatic S, Ma’ayan A, Mocco J, Faries P, Merad M, Giannarelli C (2019) Single-cell immune landscape of human atherosclerotic plaques. Nat Med 25:1576–1588. https://doi.org/10.1038/s41591-019-0590-4CrossRefPubMedPubMedCentral

19.

Gordon D, Reidy MA, Benditt EP, Schwartz SM (1990) Cell proliferation in human coronary arteries. Proc Natl Acad Sci USA 87:4600–4604. https://doi.org/10.1073/pnas.87.12.4600CrossRefPubMedPubMedCentral

20.

Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SCJ, Sperling L, Virani SS, Yeboah J (2018) 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: a report of the American college of cardiology/American heart association task force on clinical practice guidelines. J Am Coll Cardiol 73:e285–e350. https://doi.org/10.1016/j.jacc.2018.11.003CrossRefPubMed

21.

Haka AS, Potteaux S, Fraser H, Randolph GJ, Maxfield FR (2012) Quantitative analysis of monocyte subpopulations in murine atherosclerotic plaques by multiphoton microscopy. PLoS ONE 7:e44823. https://doi.org/10.1371/journal.pone.0044823CrossRefPubMedPubMedCentral

22.

Kim K, Shim D, Lee JS, Zaitsev K, Williams JW, Kim K-W, Jang M-Y, Seok Jang H, Yun TJ, Lee SH, Yoon WK, Prat A, Seidah NG, Choi J, Lee S-P, Yoon S-H, Nam JW, Seong JK, Oh GT, Randolph GJ, Artyomov MN, Cheong C, Choi J-H (2018) Transcriptome analysis reveals nonfoamy rather than foamy plaque macrophages are proinflammatory in atherosclerotic murine models. Circ Res 123:1127–1142. https://doi.org/10.1161/CIRCRESAHA.118.312804CrossRefPubMedPubMedCentral

23.

Kinlay S (2007) Low-density lipoprotein-dependent and -independent effects of cholesterol-lowering therapies on C-reactive protein: a meta-analysis. J Am Coll Cardiol 49:2003–2009. https://doi.org/10.1016/j.jacc.2007.01.083CrossRefPubMed

24.

Koskinas KC, Ughi GJ, Windecker S, Tearney GJ, Raber L (2016) Intracoronary imaging of coronary atherosclerosis: validation for diagnosis, prognosis and treatment. Eur Heart J 37:524–535. https://doi.org/10.1093/eurheartj/ehv642CrossRefPubMed

25.

Kühnast S, Fiocco M, van der Hoorn JW, Princen HM, Jukema JW (2015) Innovative pharmaceutical interventions in cardiovascular disease: Focusing on the contribution of non-HDL-C/LDL-C-lowering versus HDL-C-raising: A systematic review and meta-analysis of relevant preclinical studies and clinical trials. Eur J Pharmacol 763:48–63. https://doi.org/10.1016/j.ejphar.2015.03.089CrossRefPubMed

26.

Kuhnast S, van der Tuin SJ, van der Hoorn JW, van Klinken JB, Simic B, Pieterman E, Havekes LM, Landmesser U, Luscher TF, Willems van Dijk K, Rensen PC, Jukema JW, Princen HM (2015) Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin. Eur Heart J 36:39–48. https://doi.org/10.1093/eurheartj/ehu319CrossRefPubMed

27.

Lamon-Fava S, Diffenderfer MR, Barrett PH, Buchsbaum A, Matthan NR, Lichtenstein AH, Dolnikowski GG, Horvath K, Asztalos BF, Zago V, Schaefer EJ (2007) Effects of different doses of atorvastatin on human apolipoprotein B-100, B-48, and A-I metabolism. J Lipid Res 48:1746–1753. https://doi.org/10.1194/jlr.M700067-JLR200CrossRefPubMed

28.

Li W, Luehmann HP, Hsiao H-M, Tanaka S, Higashikubo R, Gauthier JM, Sultan D, Lavine KJ, Brody SL, Gelman AE, Gropler RJ, Liu Y, Kreisel D (2018) Visualization of monocytic cells in regressing atherosclerotic plaques by intravital 2-photon and positron emission tomography-based imaging—brief report. Arterioscler Thromb Vasc Biol 38:1030–1036. https://doi.org/10.1161/ATVBAHA.117.310517CrossRefPubMedPubMedCentral

29.

Lindau A, Hardtner C, Hergeth SP, Blanz KD, Dufner B, Hoppe N, Anto-Michel N, Kornemann J, Zou J, Gerhardt LM, Heidt T, Willecke F, Geis S, Stachon P, Wolf D, Libby P, Swirski FK, Robbins CS, McPheat W, Hawley S, Braddock M, Gilsbach R, Hein L, von zur Muhlen C, Bode C, Zirlik A, Hilgendorf I (2016) Atheroprotection through SYK inhibition fails in established disease when local macrophage proliferation dominates lesion progression. Basic Res Cardiol 111:20. https://doi.org/10.1007/s00395-016-0535-8CrossRefPubMedPubMedCentral

30.

Llodra J, Angeli V, Liu J, Trogan E, Fisher EA, Randolph GJ (2004) Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc Natl Acad Sci U S A 101:11779–11784. https://doi.org/10.1073/pnas.0403259101CrossRefPubMedPubMedCentral

31.

McArdle S, Buscher K, Ghosheh Y, Pramod AB, Miller J, Winkels H, Wolf D, Ley K (2019) Migratory and dancing macrophage subsets in atherosclerotic lesions. Circ Res 125:1038–1051. https://doi.org/10.1161/CIRCRESAHA.119.315175CrossRefPubMedPubMedCentral

32.

Moore KJ, Koplev S, Fisher EA, Tabas I, Bjorkegren JLM, Doran AC, Kovacic JC (2018) Macrophage trafficking, inflammatory resolution, and genomics in atherosclerosis: JACC macrophage in CVD series (Part 2). J Am Coll Cardiol 72:2181–2197. https://doi.org/10.1016/j.jacc.2018.08.2147CrossRefPubMedPubMedCentral

33.

Murphy AJ, Akhtari M, Tolani S, Pagler T, Bijl N, Kuo CL, Wang M, Sanson M, Abramowicz S, Welch C, Bochem AE, Kuivenhoven JA, Yvan-Charvet L, Tall AR (2011) ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J Clin Invest 121:4138–4149. https://doi.org/10.1172/JCI57559CrossRefPubMedPubMedCentral

34.

Nachtigal P, Jamborova G, Pospisilova N, Pospechova K, Solichova D, Zdansky P, Semecky V (2006) Atorvastatin has distinct effects on endothelial markers in different mouse models of atherosclerosis. J Pharm Pharm Sci 9:222–230PubMed

35.

Nachtigal P, Pospisilova N, Jamborova G, Pospechova K, Solichova D, Andrys C, Zdansky P, Micuda S, Semecky V (2008) Atorvastatin has hypolipidemic and anti-inflammatory effects in apoE/LDL receptor-double-knockout mice. Life Sci 82:708–717. https://doi.org/10.1016/j.lfs.2008.01.006CrossRefPubMed

36.

Nair AB, Jacob S (2016) A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 7:27–31. https://doi.org/10.4103/0976-0105.177703CrossRefPubMedPubMedCentral

37.

Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL (2013) Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 61:404–410. https://doi.org/10.1016/j.jacc.2012.10.027CrossRefPubMed

38.

Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, The SHK, Xu XF, Ireland MA, Lenderink T, Latchem D, Hoogslag P, Jerzewski A, Nierop P, Whelan A, Hendriks R, Swart H, Schaap J, Kuijper AFM, van Hessen MWJ, Saklani P, Tan I, Thompson AG, Morton A, Judkins C, Bax WA, Dirksen M, Alings M, Hankey GJ, Budgeon CA, Tijssen JGP, Cornel JH, Thompson PL, LoDoCo2 T I (2020) Colchicine in patients with chronic coronary disease. N Engl J Med. https://doi.org/10.1056/NEJMoa2021372CrossRefPubMed

39.

Nie P, Li D, Hu L, Jin S, Yu Y, Cai Z, Shao Q, Shen J, Yi J, Xiao H, Shen L, He B (2014) Atorvastatin improves plaque stability in ApoE-knockout mice by regulating chemokines and chemokine receptors. PLoS ONE 9:e97009. https://doi.org/10.1371/journal.pone.0097009CrossRefPubMedPubMedCentral

40.

Oesterle A, Laufs U, Liao JK (2017) Pleiotropic effects of statins on the cardiovascular system. Circ Res 120:229–243. https://doi.org/10.1161/CIRCRESAHA.116.308537CrossRefPubMedPubMedCentral

41.

Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney MT, Corra U, Cosyns B, Deaton C, Graham I, Hall MS, Hobbs FDR, Lochen ML, Lollgen H, Marques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N, Smulders Y, Tiberi M, van der Worp HB, van Dis I, Verschuren WMM, Binno S (2016) 2016 European guidelines on cardiovascular disease prevention in clinical practice: the sixth joint task force of the European society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts)developed with the special contribution of the European association for cardiovascular prevention and rehabilitation (EACPR). Eur Heart J 37:2315–2381. https://doi.org/10.1093/eurheartj/ehw106CrossRefPubMedPubMedCentral

42.

Potteaux S, Gautier EL, Hutchison SB, van Rooijen N, Rader DJ, Thomas MJ, Sorci-Thomas MG, Randolph GJ (2011) Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe-/- mice during disease regression. J Clin Invest 121:2025–2036. https://doi.org/10.1172/JCI43802CrossRefPubMedPubMedCentral

43.

Rahman K, Vengrenyuk Y, Ramsey SA, Vila NR, Girgis NM, Liu J, Gusarova V, Gromada J, Weinstock A, Moore KJ, Loke P, Fisher EA (2017) Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression. J Clin Invest 127:2904–2915. https://doi.org/10.1172/JCI75005CrossRefPubMedPubMedCentral

44.

Rajavashisth TB, Andalibi A, Territo MC, Berliner JA, Navab M, Fogelman AM, Lusis AJ (1990) Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature 344:254–257. https://doi.org/10.1038/344254a0CrossRefPubMed

45.

Rekhter MD, Gordon D (1995) Active proliferation of different cell types, including lymphocytes, in human atherosclerotic plaques. Am J Pathol 147:668–677PubMedPubMedCentral

46.

Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, Mam V, Hasan A, Rosenberg Y, Iturriaga E, Gupta M, Tsigoulis M, Verma S, Clearfield M, Libby P, Goldhaber SZ, Seagle R, Ofori C, Saklayen M, Butman S, Singh N, Le May M, Bertrand O, Johnston J, Paynter NP, Glynn RJ (2018) Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. https://doi.org/10.1056/NEJMoa1809798CrossRefPubMedPubMedCentral

47.

Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, GlynnCantos RJTG (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377:1119–1131. https://doi.org/10.1056/NEJMoa1707914CrossRefPubMed

48.

Ridker PM, Libby P, MacFadyen JG, Thuren T, Ballantyne C, Fonseca F, Koenig W, Shimokawa H, Everett BM, Glynn RJ (2018) Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the canakinumab anti-inflammatory thrombosis outcomes study (CANTOS). Eur Heart J 39:3499–3507. https://doi.org/10.1093/eurheartj/ehy310CrossRefPubMed

49.

Robbins CS, Hilgendorf I, Weber GF, Theurl I, Iwamoto Y, Figueiredo JL, Gorbatov R, Sukhova GK, Gerhardt LM, Smyth D, Zavitz CC, Shikatani EA, Parsons M, van Rooijen N, Lin HY, Husain M, Libby P, Nahrendorf M, Weissleder R, Swirski FK (2013) Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med 19:1166–1172. https://doi.org/10.1038/nm.3258CrossRefPubMedPubMedCentral

50.

Rosenfeld ME, Ross R (1990) Macrophage and smooth muscle cell proliferation in atherosclerotic lesions of WHHL and comparably hypercholesterolemic fat-fed rabbits. Arteriosclerosis 10:680–687. https://doi.org/10.1161/01.atv.10.5.680CrossRefPubMed

51.

Roth L, Rombouts M, Schrijvers DM, Martinet W, De Meyer GR (2016) Cholesterol-independent effects of atorvastatin prevent cardiovascular morbidity and mortality in a mouse model of atherosclerotic plaque rupture. Vascul Pharmacol 80:50–58. https://doi.org/10.1016/j.vph.2016.01.007CrossRefPubMed

52.

Sakai M, Kobori S, Matsumura T, Biwa T, Sato Y, Takemura T, Hakamata H, Horiuchi S, Shichiri M (1997) HMG-CoA reductase inhibitors suppress macrophage growth induced by oxidized low density lipoprotein. Atherosclerosis 133:51–59. https://doi.org/10.1016/s0021-9150(97)00118-4CrossRefPubMed

53.

Schaefer EJ, McNamara JR, Tayler T, Daly JA, Gleason JL, Seman LJ, Ferrari A, Rubenstein JJ (2004) Comparisons of effects of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) on fasting and postprandial lipoproteins in patients with coronary heart disease versus control subjects. Am J Cardiol 93:31–39. https://doi.org/10.1016/j.amjcard.2003.09.008CrossRefPubMed

54.

Shankman LS, Gomez D, Cherepanova OA, Salmon M, Alencar GF, Haskins RM, Swiatlowska P, Newman AA, Greene ES, Straub AC, Isakson B, Randolph GJ, Owens GK (2015) KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat Med 21:628–637. https://doi.org/10.1038/nm.3866CrossRefPubMedPubMedCentral

55.

Sharma M, Schlegel MP, Afonso MS, Brown EJ, Rahman K, Weinstock A, Sansbury B, Corr EM, van Solingen C, Koelwyn G, Shanley LC, Beckett L, Peled D, Lafaille JJ, Spite M, Loke P, Fisher EA, Moore KJ (2020) Regulatory T cells license macrophage pro-resolving functions during atherosclerosis regression. Circ Res. https://doi.org/10.1161/CIRCRESAHA.119.316461CrossRefPubMedPubMedCentral

56.

Shiozaki AA, Senra T, Morikawa AT, Deus DF, Paladino-Filho AT, Pinto IM, Maranhao RC (2016) Treatment of patients with aortic atherosclerotic disease with paclitaxel-associated lipid nanoparticles. Clinics (Sao Paulo) 71:435–439. https://doi.org/10.6061/clinics/2016(08)05CrossRef

57.

Sinha SK, Miikeda A, Fouladian Z, Mehrabian M, Edillor C, Shih D, Zhou Z, Paul MK, Charugundla S, Davis RC, Rajavashisth TB, Lusis AJ (2020) Local M-CSF (macrophage colony-stimulating factor) expression regulates macrophage proliferation and apoptosis in atherosclerosis. Arterioscler Thromb Vasc Biol. https://doi.org/10.1161/ATVBAHA.120.315255CrossRefPubMedPubMedCentral

58.

Sniderman AD, Thanassoulis G, Glavinovic T, Navar AM, Pencina M, Catapano A, Ference BA (2019) Apolipoprotein B particles and cardiovascular disease: a narrative review. JAMA Cardiol 4:1287–1295. https://doi.org/10.1001/jamacardio.2019.3780CrossRefPubMedPubMedCentral

59.

Tang J, Lobatto ME, Hassing L, van der Staay S, van Rijs SM, Calcagno C, Braza MS, Baxter S, Fay F, Sanchez-Gaytan BL, Duivenvoorden R, Sager H, Astudillo YM, Leong W, Ramachandran S, Storm G, Perez-Medina C, Reiner T, Cormode DP, Strijkers GJ, Stroes ES, Swirski FK, Nahrendorf M, Fisher EA, Fayad ZA, Mulder WJ (2015) Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation. Sci Adv. https://doi.org/10.1126/sciadv.1400223CrossRefPubMedPubMedCentral

60.

Tang TY, Howarth SP, Miller SR, Graves MJ, Patterson AJ, U-King-Im JM, Li ZY, Walsh SR, Brown AP, Kirkpatrick PJ, Warburton EA, Hayes PD, Varty K, Boyle JR, Gaunt ME, Zalewski A, Gillard JH (2009) The ATHEROMA (Atorvastatin therapy: effects on reduction of macrophage activity) study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease. J Am Coll Cardiol 53:2039–2050. https://doi.org/10.1016/j.jacc.2009.03.018CrossRefPubMed

61.

Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto FJ, Ibrahim R, Gamra H, Kiwan GS, Berry C, López-Sendón J, Ostadal P, Koenig W, Angoulvant D, Grégoire JC, Lavoie MA, Dubé MP, Rhainds D, Provencher M, Blondeau L, Orfanos A, L’Allier PL, Guertin MC, Roubille F (2019) Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 381:2497–2505. https://doi.org/10.1056/NEJMoa1912388CrossRefPubMed

62.

Tuomisto TT, Lumivuori H, Kansanen E, Hakkinen SK, Turunen MP, van Thienen JV, Horrevoets AJ, Levonen AL, Yla-Herttuala S (2008) Simvastatin has an anti-inflammatory effect on macrophages via upregulation of an atheroprotective transcription factor, Kruppel-like factor 2. Cardiovasc Res 78:175–184. https://doi.org/10.1093/cvr/cvn007CrossRefPubMed

63.

van Vlijmen BJ, van ‘t Hof HB, Mol MJ, van der Boom H, van der Zee A, Frants RR, Hofker MH, Havekes LM (1996) Modulation of very low density lipoprotein production and clearance contributes to age- and gender- dependent hyperlipoproteinemia in apolipoprotein E3-Leiden transgenic mice. J Clin Invest 97:1184–1192. https://doi.org/10.1172/JCI118532CrossRefPubMedPubMedCentral

64.

Verschuren L, Kleemann R, Offerman EH, Szalai AJ, Emeis SJ, Princen HM, Kooistra T (2005) Effect of low dose atorvastatin versus diet-induced cholesterol lowering on atherosclerotic lesion progression and inflammation in apolipoprotein E*3-Leiden transgenic mice. Arterioscler Thromb Vasc Biol 25:161–167. https://doi.org/10.1161/01.ATV.0000148866.29829.19CrossRefPubMed

65.

Weinberger T, Esfandyari D, Messerer D, Percin G, Schleifer C, Thaler R, Liu L, Stremmel C, Schneider V, Vagnozzi RJ, Schwanenkamp J, Fischer M, Busch K, Klapproth K, Ishikawa-Ankerhold H, Klösges L, Titova A, Molkentin JD, Kobayashi Y, Engelhardt S, Massberg S, Waskow C, Perdiguero EG, Schulz C (2020) Ontogeny of arterial macrophages defines their functions in homeostasis and inflammation. Nat Commun 11:4549. https://doi.org/10.1038/s41467-020-18287-xCrossRefPubMedPubMedCentral

66.

Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J, Bruns C, Cottens S, Takada Y, Hommel U (2001) Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 7:687–692. https://doi.org/10.1038/89058CrossRefPubMed

67.

Williams JW, Martel C, Potteaux S, Esaulova E, Ingersoll MA, Elvington A, Saunders BT, Huang LH, Habenicht AJ, Zinselmeyer BH, Randolph GJ (2018) Limited macrophage positional dynamics in progressing or regressing murine atherosclerotic plaques-brief report. Arterioscler Thromb Vasc Biol 38:1702–1710. https://doi.org/10.1161/ATVBAHA.118.311319CrossRefPubMedPubMedCentral

68.

Williams JW, Zaitsev K, Kim KW, Ivanov S, Saunders BT, Schrank PR, Kim K, Elvington A, Kim SH, Tucker CG, Wohltmann M, Fife BT, Epelman S, Artyomov MN, Lavine KJ, Zinselmeyer BH, Choi JH, Randolph GJ (2020) Limited proliferation capacity of aortic intima resident macrophages requires monocyte recruitment for atherosclerotic plaque progression. Nat Immunol 21:1194–1204. https://doi.org/10.1038/s41590-020-0768-4CrossRefPubMedPubMedCentral

69.

Yin W, Carballo-Jane E, McLaren DG, Mendoza VH, Gagen K, Geoghagen NS, McNamara LA, Gorski JN, Eiermann GJ, Petrov A, Wolff M, Tong X, Wilsie LC, Akiyama TE, Chen J, Thankappan A, Xue J, Ping X, Andrews G, Wickham LA, Gai CL, Trinh T, Kulick AA, Donnelly MJ, Voronin GO, Rosa R, Cumiskey AM, Bekkari K, Mitnaul LJ, Puig O, Chen F, Raubertas R, Wong PH, Hansen BC, Koblan KS, Roddy TP, Hubbard BK, Strack AM (2012) Plasma lipid profiling across species for the identification of optimal animal models of human dyslipidemia. J Lipid Res 53:51–65. https://doi.org/10.1194/jlr.M019927CrossRefPubMedPubMedCentral

70.

Zadelaar S, Kleemann R, Verschuren L, de Vries-Van der Weij J, van der Hoorn J, Princen HM, Kooistra T (2007) Mouse models for atherosclerosis and pharmaceutical modifiers. Arterioscler Thromb Vasc Biol 27:1706–1721. https://doi.org/10.1161/ATVBAHA.107.142570CrossRefPubMed

71.

Zernecke A, Winkels H, Cochain C, Williams JW, Wolf D, Soehnlein O, Robbins CS, Monaco C, Park I, McNamara CA, Binder CJ, Cybulsky MI, Scipione CA, Hedrick CC, Galkina EV, Kyaw T, Ghosheh Y, Dinh HQ, Ley K (2020) Meta-analysis of leukocyte diversity in atherosclerotic mouse aortas. Circ Res 127:402–426. https://doi.org/10.1161/CIRCRESAHA.120.316903CrossRefPubMedPubMedCentral

Title: Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering
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
Publication date: 01-12-2020
Publisher: Springer Berlin Heidelberg
Keywords: Atorvastatin
Arterial Occlusive Disease
Published in: Basic Research in Cardiology / Issue 6/2020
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-020-00838-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2020

PCSK9 regulates pyroptosis via mtDNA damage in chronic myocardial ischemia

Mouse models of atherosclerosis and their suitability for the study of myocardial infarction

Functional investigation of the coronary artery disease gene SVEP1

Deletion of obscurin immunoglobulin domains Ig58/59 leads to age-dependent cardiac remodeling and arrhythmia

The six-transmembrane protein Stamp2 ameliorates pulmonary vascular remodeling and pulmonary hypertension in mice

Genetic background influences expression and function of the cation channel TRPM4 in the mouse heart