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

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

Author information

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.

PMID:
29016683
PMCID:
PMC5634597
DOI:
10.1371/journal.pone.0185820
[Indexed for MEDLINE]
Free PMC Article

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