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

doi:10.1371/journal.pone.0185820

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

PLoS One. 2017 Oct 10;12(10):e0185820. doi: 10.1371/journal.pone.0185820. eCollection 2017.

Authors

Rob C M de Jong^{1

2}, Mark M Ewing^{1

3}, Margreet R de Vries^{1

2}, Jacco C Karper^{1

2}, Antonius J N M Bastiaansen^{1

2}, Hendrika A B Peters^{1

2}, Fabiana Baghana^{1

2}, Peter J van den Elsen^{4

5}, Céline Gongora^{6

7}, J Wouter Jukema^{2

3}, Paul H A Quax^{1

2}

Affiliations

¹ Department of Surgery, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
² Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
³ Department of Cardiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
⁴ Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
⁵ Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
⁶ Université de Montpellier 2, Montpellier, France.
⁷ Institut de Recherche en Cancérologie de Montpellier INSERM U 89, Montpellier, France.

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.

MeSH terms

Animals
Apolipoproteins E / genetics
Apolipoproteins E / metabolism
Cell Adhesion / drug effects
Chemokine CCL2 / genetics
Chemokine CCL2 / metabolism
Disease Models, Animal
Epigenesis, Genetic*
Femoral Artery / drug effects
Femoral Artery / metabolism
Femoral Artery / pathology
Humans
Hyperplasia / genetics
Hyperplasia / metabolism
Hyperplasia / pathology
Hyperplasia / prevention & control*
Interleukin-6 / genetics
Interleukin-6 / metabolism
Leukocytes / drug effects
Leukocytes / metabolism
Leukocytes / pathology
Macrophages / drug effects
Macrophages / metabolism
Macrophages / pathology
Male
Mice
Mice, Knockout
Myocytes, Smooth Muscle / drug effects
Myocytes, Smooth Muscle / metabolism
Myocytes, Smooth Muscle / pathology
NF-kappa B / genetics
NF-kappa B / metabolism
Primary Cell Culture
Signal Transduction
Terpenes / pharmacology*
Tumor Necrosis Factor-alpha / genetics
Tumor Necrosis Factor-alpha / metabolism
Tunica Intima / drug effects
Tunica Intima / metabolism
Tunica Intima / pathology
Vasculitis / genetics
Vasculitis / metabolism
Vasculitis / pathology
Vasculitis / prevention & control*
p300-CBP Transcription Factors / antagonists & inhibitors
p300-CBP Transcription Factors / deficiency
p300-CBP Transcription Factors / genetics*

Substances

Apolipoproteins E
Ccl2 protein, mouse
Chemokine CCL2
Interleukin-6
NF-kappa B
Terpenes
Tumor Necrosis Factor-alpha
interleukin-6, mouse
p300-CBP Transcription Factors
p300-CBP-associated factor
garcinol

Grants and funding

This work was supported by the Netherlands CardioVascular Research Initiative: “the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences" for the GENIUS project “Generating the best evidence-based pharmaceutical targets for atherosclerosis” (CVON2011-19).