Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation

Jun Tang, Mark E. Lobatto, Laurien Hassing, Susanne Van Der Staay, Sarian M. Van Rijs, Claudia Calcagno, Mounia S. Braza, Samantha Baxter, Francois Fay, Brenda L. Sanchez-Gaytan, Raphaël Duivenvoorden, Hendrik B. Sager, Yaritzy M. Astudillo, Wei Leong, Sarayu Ramachandran, Gert Storm, Carlos Pérez-Medina, Thomas Reiner, David P. Cormode, Gustav J. Strijkers & 6 others Erik S.G. Stroes, Filip K. Swirski, Matthias Nahrendorf, Edward A. Fisher, Zahi A. Fayad, Willem J.M. Mulder

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Abstract

Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking bloodmonocyte recruitment to the plaque or increasing macrophage apoptosis and emigration. Becausemacrophage proliferation was recently shown to dominatemacrophage accumulation in advanced plaques, locally inhibitingmacrophage proliferationmay reduce plaque inflammation and produce long-term therapeutic benefits. To test this hypothesis, we used nanoparticle-based delivery of simvastatin to inhibit plaque macrophage proliferation in apolipoprotein E-deficientmice (Apoe-/-)with advanced atherosclerotic plaques. This resulted in the rapid reduction of plaque inflammation and favorable phenotype remodeling. We then combined this short-term nanoparticle intervention with an 8-week oral statin treatment, and this regimen rapidly reduced and continuously suppressed plaque inflammation. Our results demonstrate that pharmacologically inhibiting localmacrophage proliferation can effectively treat inflammation in atherosclerosis.

Original languageEnglish
Article numbere1400223
JournalScience advances
Volume1
Issue number3
DOIs
Publication statusPublished - 1 Apr 2015

Fingerprint

Atherosclerotic Plaques
Macrophages
Inflammation
Nanoparticles
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Simvastatin
Emigration and Immigration
Apolipoproteins E
Rupture
Atherosclerosis
Apoptosis
Phenotype
Therapeutics

Cite this

Tang, J., Lobatto, M. E., Hassing, L., Van Der Staay, S., Van Rijs, S. M., Calcagno, C., ... Mulder, W. J. M. (2015). Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation. Science advances, 1(3), [e1400223]. https://doi.org/10.1126/sciadv.1400223
Tang, Jun ; Lobatto, Mark E. ; Hassing, Laurien ; Van Der Staay, Susanne ; Van Rijs, Sarian M. ; Calcagno, Claudia ; Braza, Mounia S. ; Baxter, Samantha ; Fay, Francois ; Sanchez-Gaytan, Brenda L. ; Duivenvoorden, Raphaël ; Sager, Hendrik B. ; Astudillo, Yaritzy M. ; Leong, Wei ; Ramachandran, Sarayu ; Storm, Gert ; Pérez-Medina, Carlos ; Reiner, Thomas ; Cormode, David P. ; Strijkers, Gustav J. ; Stroes, Erik S.G. ; Swirski, Filip K. ; Nahrendorf, Matthias ; Fisher, Edward A. ; Fayad, Zahi A. ; Mulder, Willem J.M. / Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation. In: Science advances. 2015 ; Vol. 1, No. 3.
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abstract = "Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking bloodmonocyte recruitment to the plaque or increasing macrophage apoptosis and emigration. Becausemacrophage proliferation was recently shown to dominatemacrophage accumulation in advanced plaques, locally inhibitingmacrophage proliferationmay reduce plaque inflammation and produce long-term therapeutic benefits. To test this hypothesis, we used nanoparticle-based delivery of simvastatin to inhibit plaque macrophage proliferation in apolipoprotein E-deficientmice (Apoe-/-)with advanced atherosclerotic plaques. This resulted in the rapid reduction of plaque inflammation and favorable phenotype remodeling. We then combined this short-term nanoparticle intervention with an 8-week oral statin treatment, and this regimen rapidly reduced and continuously suppressed plaque inflammation. Our results demonstrate that pharmacologically inhibiting localmacrophage proliferation can effectively treat inflammation in atherosclerosis.",
author = "Jun Tang and Lobatto, {Mark E.} and Laurien Hassing and {Van Der Staay}, Susanne and {Van Rijs}, {Sarian M.} and Claudia Calcagno and Braza, {Mounia S.} and Samantha Baxter and Francois Fay and Sanchez-Gaytan, {Brenda L.} and Rapha{\"e}l Duivenvoorden and Sager, {Hendrik B.} and Astudillo, {Yaritzy M.} and Wei Leong and Sarayu Ramachandran and Gert Storm and Carlos P{\'e}rez-Medina and Thomas Reiner and Cormode, {David P.} and Strijkers, {Gustav J.} and Stroes, {Erik S.G.} and Swirski, {Filip K.} and Matthias Nahrendorf and Fisher, {Edward A.} and Fayad, {Zahi A.} and Mulder, {Willem J.M.}",
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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, HB, Astudillo, YM, Leong, W, Ramachandran, S, Storm, G, Pérez-Medina, C, Reiner, T, Cormode, DP, Strijkers, GJ, Stroes, ESG, Swirski, FK, Nahrendorf, M, Fisher, EA, Fayad, ZA & Mulder, WJM 2015, 'Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation' Science advances, vol. 1, no. 3, e1400223. https://doi.org/10.1126/sciadv.1400223

Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation. / Tang, Jun; Lobatto, Mark E.; Hassing, Laurien; Van Der Staay, Susanne; Van Rijs, Sarian M.; Calcagno, Claudia; Braza, Mounia S.; Baxter, Samantha; Fay, Francois; Sanchez-Gaytan, Brenda L.; Duivenvoorden, Raphaël; Sager, Hendrik B.; Astudillo, Yaritzy M.; Leong, Wei; Ramachandran, Sarayu; Storm, Gert; Pérez-Medina, Carlos; Reiner, Thomas; Cormode, David P.; Strijkers, Gustav J.; Stroes, Erik S.G.; Swirski, Filip K.; Nahrendorf, Matthias; Fisher, Edward A.; Fayad, Zahi A.; Mulder, Willem J.M.

In: Science advances, Vol. 1, No. 3, e1400223, 01.04.2015.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation

AU - Tang, Jun

AU - Lobatto, Mark E.

AU - Hassing, Laurien

AU - Van Der Staay, Susanne

AU - Van Rijs, Sarian M.

AU - Calcagno, Claudia

AU - Braza, Mounia S.

AU - Baxter, Samantha

AU - Fay, Francois

AU - Sanchez-Gaytan, Brenda L.

AU - Duivenvoorden, Raphaël

AU - Sager, Hendrik B.

AU - Astudillo, Yaritzy M.

AU - Leong, Wei

AU - Ramachandran, Sarayu

AU - Storm, Gert

AU - Pérez-Medina, Carlos

AU - Reiner, Thomas

AU - Cormode, David P.

AU - Strijkers, Gustav J.

AU - Stroes, Erik S.G.

AU - Swirski, Filip K.

AU - Nahrendorf, Matthias

AU - Fisher, Edward A.

AU - Fayad, Zahi A.

AU - Mulder, Willem J.M.

PY - 2015/4/1

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AB - Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking bloodmonocyte recruitment to the plaque or increasing macrophage apoptosis and emigration. Becausemacrophage proliferation was recently shown to dominatemacrophage accumulation in advanced plaques, locally inhibitingmacrophage proliferationmay reduce plaque inflammation and produce long-term therapeutic benefits. To test this hypothesis, we used nanoparticle-based delivery of simvastatin to inhibit plaque macrophage proliferation in apolipoprotein E-deficientmice (Apoe-/-)with advanced atherosclerotic plaques. This resulted in the rapid reduction of plaque inflammation and favorable phenotype remodeling. We then combined this short-term nanoparticle intervention with an 8-week oral statin treatment, and this regimen rapidly reduced and continuously suppressed plaque inflammation. Our results demonstrate that pharmacologically inhibiting localmacrophage proliferation can effectively treat inflammation in atherosclerosis.

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Tang J, Lobatto ME, Hassing L, Van Der Staay S, Van Rijs SM, Calcagno C et al. Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation. Science advances. 2015 Apr 1;1(3). e1400223. https://doi.org/10.1126/sciadv.1400223