The epigenetic factor PCAF regulates vascular inflammation and is essential for intimal hyperplasia development

Rob C.M. De Jong, Mark M. Ewing, Margreet R. De Vries, Jacco C. Karper, Antonius J.N.M. Bastiaansen, Hendrika A.B. Peters, Fabiana Baghana, Peter J. Van Den Elsen, Céline Gongora, J. Wouter Jukema, Paul H.A. Quax

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Objective: Genetic P300/CBP-associated factor (PCAF) variation affects restenosis-risk in patients. PCAF has lysine acetyltransferase activity and promotes nuclear factor kappa-beta (NFκB)mediated inflammation, which drives post-interventional intimal hyperplasia development. We studied the contributing role of PCAF in post-interventional intimal hyperplasia. Methods and results: PCAF contribution to inflammation and intimal hyperplasia was assessed in leukocytes, macrophages and vascular smooth muscle cells (vSMCs) in vitro and in a mouse model for intimal hyperplasia, in which a cuff is placed around the femoral artery. PCAF deficiency downregulate CCL2, IL-6 and TNF-alpha expression, as demonstrated on cultured vSMCs, leukocytes and macrophages. PCAF KO mice showed a 71.8% reduction of vSMC-rich intimal hyperplasia, a 73.4% reduction of intima/media ratio and a 63.7% reduction of luminal stenosis after femoral artery cuff placement compared to wild type (WT) mice. The association of PCAF and vascular inflammation was further investigated using the potent natural PCAF inhibitor garcinol. Garcinol treatment reduced CCL2 and TNF-alpha expression, as demonstrated on cultured vSMCs and leukocytes. To assess the effect of garcinol treatment on vascular inflammation we used hypercholesterolemic ApoE*3-Leiden mice. After cuff placement, garcinol treatment resulted in reduced arterial leukocyte and macrophage adherence and infiltration after three days compared to untreated animals. Conclusions: These results identify a vital role for the lysine acetyltransferase PCAF in the regulation of local inflammation after arterial injury and likely the subsequent vSMC proliferation, responsible for intimal hyperplasia.

Original languageEnglish
Article numbere0185820
JournalPLoS ONE
Volume12
Issue number10
DOIs
Publication statusPublished - 1 Oct 2017

Cite this

De Jong, R. C. M., Ewing, M. M., De Vries, M. R., Karper, J. C., Bastiaansen, A. J. N. M., Peters, H. A. B., ... Quax, P. H. A. (2017). The epigenetic factor PCAF regulates vascular inflammation and is essential for intimal hyperplasia development. PLoS ONE, 12(10), [e0185820]. https://doi.org/10.1371/journal.pone.0185820
De Jong, Rob C.M. ; Ewing, Mark M. ; De Vries, Margreet R. ; Karper, Jacco C. ; Bastiaansen, Antonius J.N.M. ; Peters, Hendrika A.B. ; Baghana, Fabiana ; Van Den Elsen, Peter J. ; Gongora, Céline ; Jukema, J. Wouter ; Quax, Paul H.A. / The epigenetic factor PCAF regulates vascular inflammation and is essential for intimal hyperplasia development. In: PLoS ONE. 2017 ; Vol. 12, No. 10.
@article{81950c56130746d08bb13564a8833a41,
title = "The epigenetic factor PCAF regulates vascular inflammation and is essential for intimal hyperplasia development",
abstract = "Objective: Genetic P300/CBP-associated factor (PCAF) variation affects restenosis-risk in patients. PCAF has lysine acetyltransferase activity and promotes nuclear factor kappa-beta (NFκB)mediated inflammation, which drives post-interventional intimal hyperplasia development. We studied the contributing role of PCAF in post-interventional intimal hyperplasia. Methods and results: PCAF contribution to inflammation and intimal hyperplasia was assessed in leukocytes, macrophages and vascular smooth muscle cells (vSMCs) in vitro and in a mouse model for intimal hyperplasia, in which a cuff is placed around the femoral artery. PCAF deficiency downregulate CCL2, IL-6 and TNF-alpha expression, as demonstrated on cultured vSMCs, leukocytes and macrophages. PCAF KO mice showed a 71.8{\%} reduction of vSMC-rich intimal hyperplasia, a 73.4{\%} reduction of intima/media ratio and a 63.7{\%} reduction of luminal stenosis after femoral artery cuff placement compared to wild type (WT) mice. The association of PCAF and vascular inflammation was further investigated using the potent natural PCAF inhibitor garcinol. Garcinol treatment reduced CCL2 and TNF-alpha expression, as demonstrated on cultured vSMCs and leukocytes. To assess the effect of garcinol treatment on vascular inflammation we used hypercholesterolemic ApoE*3-Leiden mice. After cuff placement, garcinol treatment resulted in reduced arterial leukocyte and macrophage adherence and infiltration after three days compared to untreated animals. Conclusions: These results identify a vital role for the lysine acetyltransferase PCAF in the regulation of local inflammation after arterial injury and likely the subsequent vSMC proliferation, responsible for intimal hyperplasia.",
author = "{De Jong}, {Rob C.M.} and Ewing, {Mark M.} and {De Vries}, {Margreet R.} and Karper, {Jacco C.} and Bastiaansen, {Antonius J.N.M.} and Peters, {Hendrika A.B.} and Fabiana Baghana and {Van Den Elsen}, {Peter J.} and C{\'e}line Gongora and Jukema, {J. Wouter} and Quax, {Paul H.A.}",
year = "2017",
month = "10",
day = "1",
doi = "10.1371/journal.pone.0185820",
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De Jong, RCM, Ewing, MM, De Vries, MR, Karper, JC, Bastiaansen, AJNM, Peters, HAB, Baghana, F, Van Den Elsen, PJ, Gongora, C, Jukema, JW & Quax, PHA 2017, 'The epigenetic factor PCAF regulates vascular inflammation and is essential for intimal hyperplasia development' PLoS ONE, vol. 12, no. 10, e0185820. https://doi.org/10.1371/journal.pone.0185820

The epigenetic factor PCAF regulates vascular inflammation and is essential for intimal hyperplasia development. / De Jong, Rob C.M.; Ewing, Mark M.; De Vries, Margreet R.; Karper, Jacco C.; Bastiaansen, Antonius J.N.M.; Peters, Hendrika A.B.; Baghana, Fabiana; Van Den Elsen, Peter J.; Gongora, Céline; Jukema, J. Wouter; Quax, Paul H.A.

In: PLoS ONE, Vol. 12, No. 10, e0185820, 01.10.2017.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The epigenetic factor PCAF regulates vascular inflammation and is essential for intimal hyperplasia development

AU - De Jong, Rob C.M.

AU - Ewing, Mark M.

AU - De Vries, Margreet R.

AU - Karper, Jacco C.

AU - Bastiaansen, Antonius J.N.M.

AU - Peters, Hendrika A.B.

AU - Baghana, Fabiana

AU - Van Den Elsen, Peter J.

AU - Gongora, Céline

AU - Jukema, J. Wouter

AU - Quax, Paul H.A.

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Objective: Genetic P300/CBP-associated factor (PCAF) variation affects restenosis-risk in patients. PCAF has lysine acetyltransferase activity and promotes nuclear factor kappa-beta (NFκB)mediated inflammation, which drives post-interventional intimal hyperplasia development. We studied the contributing role of PCAF in post-interventional intimal hyperplasia. Methods and results: PCAF contribution to inflammation and intimal hyperplasia was assessed in leukocytes, macrophages and vascular smooth muscle cells (vSMCs) in vitro and in a mouse model for intimal hyperplasia, in which a cuff is placed around the femoral artery. PCAF deficiency downregulate CCL2, IL-6 and TNF-alpha expression, as demonstrated on cultured vSMCs, leukocytes and macrophages. PCAF KO mice showed a 71.8% reduction of vSMC-rich intimal hyperplasia, a 73.4% reduction of intima/media ratio and a 63.7% reduction of luminal stenosis after femoral artery cuff placement compared to wild type (WT) mice. The association of PCAF and vascular inflammation was further investigated using the potent natural PCAF inhibitor garcinol. Garcinol treatment reduced CCL2 and TNF-alpha expression, as demonstrated on cultured vSMCs and leukocytes. To assess the effect of garcinol treatment on vascular inflammation we used hypercholesterolemic ApoE*3-Leiden mice. After cuff placement, garcinol treatment resulted in reduced arterial leukocyte and macrophage adherence and infiltration after three days compared to untreated animals. Conclusions: These results identify a vital role for the lysine acetyltransferase PCAF in the regulation of local inflammation after arterial injury and likely the subsequent vSMC proliferation, responsible for intimal hyperplasia.

AB - Objective: Genetic P300/CBP-associated factor (PCAF) variation affects restenosis-risk in patients. PCAF has lysine acetyltransferase activity and promotes nuclear factor kappa-beta (NFκB)mediated inflammation, which drives post-interventional intimal hyperplasia development. We studied the contributing role of PCAF in post-interventional intimal hyperplasia. Methods and results: PCAF contribution to inflammation and intimal hyperplasia was assessed in leukocytes, macrophages and vascular smooth muscle cells (vSMCs) in vitro and in a mouse model for intimal hyperplasia, in which a cuff is placed around the femoral artery. PCAF deficiency downregulate CCL2, IL-6 and TNF-alpha expression, as demonstrated on cultured vSMCs, leukocytes and macrophages. PCAF KO mice showed a 71.8% reduction of vSMC-rich intimal hyperplasia, a 73.4% reduction of intima/media ratio and a 63.7% reduction of luminal stenosis after femoral artery cuff placement compared to wild type (WT) mice. The association of PCAF and vascular inflammation was further investigated using the potent natural PCAF inhibitor garcinol. Garcinol treatment reduced CCL2 and TNF-alpha expression, as demonstrated on cultured vSMCs and leukocytes. To assess the effect of garcinol treatment on vascular inflammation we used hypercholesterolemic ApoE*3-Leiden mice. After cuff placement, garcinol treatment resulted in reduced arterial leukocyte and macrophage adherence and infiltration after three days compared to untreated animals. Conclusions: These results identify a vital role for the lysine acetyltransferase PCAF in the regulation of local inflammation after arterial injury and likely the subsequent vSMC proliferation, responsible for intimal hyperplasia.

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DO - 10.1371/journal.pone.0185820

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De Jong RCM, Ewing MM, De Vries MR, Karper JC, Bastiaansen AJNM, Peters HAB et al. The epigenetic factor PCAF regulates vascular inflammation and is essential for intimal hyperplasia development. PLoS ONE. 2017 Oct 1;12(10). e0185820. https://doi.org/10.1371/journal.pone.0185820