AUTHOR=de Jong Alwin , de Jong Rob C. M. , Peters Erna A. , Arens Ramon , Jukema J. Wouter , de Vries Margreet R. , Quax Paul H. A. 

TITLE=P300/CBP Associated Factor (PCAF) Deficiency Enhances Diet-Induced Atherosclerosis in ApoE3*Leiden Mice via Systemic Inhibition of Regulatory T Cells

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 7 - 2020

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2020.604821

DOI=10.3389/fcvm.2020.604821

ISSN=2297-055X

ABSTRACT=Background: Inflammatory stimuli induced by NF-kB drive atherosclerotic lesion formation. The epigenetic P300/CBP associated factor (PCAF) post-transcriptionally acetylates Foxp3, which is required for regulatory T-cell (Treg) differentiation and immune modulation. We hypothesize that PCAF deficiency affects atherosclerosis via regulation of regulatory Tregs. 
Method: ApoE*3Leiden and ApoE*3LeidenxPCAF-/- (n=20) were fed a high-fat diet (HFD) containing 1% cholesterol. Systemic FoxP3+ T cells were measured every four weeks by flow cytometry. After five-months of HFD, mice were euthanized, and heart and blood were collected. IL-6 and TNFα concentrations were measured in plasma to identify systemic inflammatory responses. Compositional and morphometrical analyses were performed on the atherosclerotic lesions in the aortic sinuses. 
Results: After five months of HFD, plasma cholesterol concentrations were not different for ApoE*3LeidenxPCAF-/- compared to ApoE*3Leiden mice. Expression of FoxP3 by systemic CD4+ T cells decreased 1.8 fold in ApoE*3LeidenxPCAF-/- after five months HFD and remained significant reduced after five months of HFD. Systemic TNFα and IL-6 concentrations were comparable, whereas the atherosclerotic lesion size in ApoE*3LeidenxPCAF-/- mice was increased by 28% compared to ApoE*3Leiden mice. In atherosclerotic lesions, no differences were observed in macrophage differentiation or VSMC content, although a small increase in collagen was identified. 
Conclusion: Our data show that PCAF deficiency resulted in a decrease in circulatory FoxP3+ regulatory T cells and ameliorated atherosclerotic lesions with no differences in systemic inflammation or macrophage differentiation in the atherosclerotic lesions. This suggests that PCAF regulates atherosclerosis via modulation of Foxp3+ regulatory T-cell differentiation.