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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

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 deficienc...

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Autores principales: de Jong, Alwin, de Jong, Rob C. M., Peters, Erna A., Arens, Ramon, Jukema, J. Wouter, de Vries, Margreet R., Quax, Paul H. A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874080/
https://www.ncbi.nlm.nih.gov/pubmed/33585580
http://dx.doi.org/10.3389/fcvm.2020.604821
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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.
author_facet de Jong, Alwin
de Jong, Rob C. M.
Peters, Erna A.
Arens, Ramon
Jukema, J. Wouter
de Vries, Margreet R.
Quax, Paul H. A.
author_sort de Jong, Alwin
collection PubMed
description 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 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 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 TNFα 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.
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spelling pubmed-78740802021-02-11 P300/CBP Associated Factor (PCAF) Deficiency Enhances Diet-Induced Atherosclerosis in ApoE3(*)Leiden Mice via Systemic Inhibition of Regulatory T Cells de Jong, Alwin de Jong, Rob C. M. Peters, Erna A. Arens, Ramon Jukema, J. Wouter de Vries, Margreet R. Quax, Paul H. A. Front Cardiovasc Med Cardiovascular Medicine 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 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 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 TNFα 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. Frontiers Media S.A. 2021-01-15 /pmc/articles/PMC7874080/ /pubmed/33585580 http://dx.doi.org/10.3389/fcvm.2020.604821 Text en Copyright © 2021 de Jong, de Jong, Peters, Arens, Jukema, de Vries and Quax. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cardiovascular Medicine
de Jong, Alwin
de Jong, Rob C. M.
Peters, Erna A.
Arens, Ramon
Jukema, J. Wouter
de Vries, Margreet R.
Quax, Paul H. A.
P300/CBP Associated Factor (PCAF) Deficiency Enhances Diet-Induced Atherosclerosis in ApoE3(*)Leiden Mice via Systemic Inhibition of Regulatory T Cells
title P300/CBP Associated Factor (PCAF) Deficiency Enhances Diet-Induced Atherosclerosis in ApoE3(*)Leiden Mice via Systemic Inhibition of Regulatory T Cells
title_full P300/CBP Associated Factor (PCAF) Deficiency Enhances Diet-Induced Atherosclerosis in ApoE3(*)Leiden Mice via Systemic Inhibition of Regulatory T Cells
title_fullStr P300/CBP Associated Factor (PCAF) Deficiency Enhances Diet-Induced Atherosclerosis in ApoE3(*)Leiden Mice via Systemic Inhibition of Regulatory T Cells
title_full_unstemmed P300/CBP Associated Factor (PCAF) Deficiency Enhances Diet-Induced Atherosclerosis in ApoE3(*)Leiden Mice via Systemic Inhibition of Regulatory T Cells
title_short P300/CBP Associated Factor (PCAF) Deficiency Enhances Diet-Induced Atherosclerosis in ApoE3(*)Leiden Mice via Systemic Inhibition of Regulatory T Cells
title_sort p300/cbp associated factor (pcaf) deficiency enhances diet-induced atherosclerosis in apoe3(*)leiden mice via systemic inhibition of regulatory t cells
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874080/
https://www.ncbi.nlm.nih.gov/pubmed/33585580
http://dx.doi.org/10.3389/fcvm.2020.604821
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