P300/CBP associated factor (PCAF) deficiency enhances diet-induced atherosclerosis in ApoE3*Leiden mice via systemic inhibition of regulatory T cells

Jong, A. de; Jong, R.C.M. de; Peters, E.A.; Arens, R.; Jukema, J.W.; Vries, M.R. de; Quax, P.H.A.

doi:doi:10.3389/fcvm.2020.604821

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: ApoE3*Leiden (n = 13) and ApoE3*LeidenxPCAF(-/-) (n = 13) were fed a high-fat diet (HFD) containing 1.25% cholesterol. Systemic FoxP3(+) T cells were measured every 4 weeks by flow cytometry (n = 6). After 5-months of HFD, mice were euthanized, and hearts and blood were collected. IL-6 and TNF alpha 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 5 months of HFD, plasma cholesterol concentrations were not different for ApoE3*LeidenxPCAF(-/-) compared to ApoE3...Show moreBackground: 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: ApoE3*Leiden (n = 13) and ApoE3*LeidenxPCAF(-/-) (n = 13) were fed a high-fat diet (HFD) containing 1.25% cholesterol. Systemic FoxP3(+) T cells were measured every 4 weeks by flow cytometry (n = 6). After 5-months of HFD, mice were euthanized, and hearts and blood were collected. IL-6 and TNF alpha 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 5 months of HFD, plasma cholesterol concentrations were not different for ApoE3*LeidenxPCAF(-/-) compared to ApoE3*Leiden mice. Expression of FoxP3 by systemic CD4(+) T cells decreased 1.8 fold in ApoE3*LeidenxPCAF(-/-) after 5 months HFD and remained significantly reduced after 5 months of HFD. Systemic TNF alpha and IL-6 concentrations were comparable, whereas the atherosclerotic lesion size in ApoE3*LeidenxPCAF(-/-) mice was increased by 28% compared to ApoE3*Leiden 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.Show less

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P300/CBP associated factor (PCAF) deficiency enhances diet-induced atherosclerosis in ApoE3*Leiden mice via systemic inhibition of regulatory T cells