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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| Format: | Article |
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Frontiers Media S.A.
2021-01-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2020.604821/full |
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| author | Alwin de Jong Alwin de Jong Rob C. M. de Jong Erna A. Peters Erna A. Peters Ramon Arens J. Wouter Jukema Margreet R. de Vries Margreet R. de Vries Paul H. A. Quax Paul H. A. Quax |
| author_facet | Alwin de Jong Alwin de Jong Rob C. M. de Jong Erna A. Peters Erna A. Peters Ramon Arens J. Wouter Jukema Margreet R. de Vries Margreet R. de Vries Paul H. A. Quax Paul H. A. Quax |
| author_sort | Alwin de Jong |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-24T05:23:10Z |
| format | Article |
| id | doaj.art-68141aef302449a18469194bd065858d |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-12-24T05:23:10Z |
| publishDate | 2021-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-68141aef302449a18469194bd065858d2022-12-21T17:13:24ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2021-01-01710.3389/fcvm.2020.604821604821P300/CBP Associated Factor (PCAF) Deficiency Enhances Diet-Induced Atherosclerosis in ApoE3*Leiden Mice via Systemic Inhibition of Regulatory T CellsAlwin de Jong0Alwin de Jong1Rob C. M. de Jong2Erna A. Peters3Erna A. Peters4Ramon Arens5J. Wouter Jukema6Margreet R. de Vries7Margreet R. de Vries8Paul H. A. Quax9Paul H. A. Quax10Department of Surgery, Leiden University Medical Center, Leiden, NetherlandsEinthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, NetherlandsDepartment of Hematology, Leiden University Medical Center, Leiden, NetherlandsDepartment of Surgery, Leiden University Medical Center, Leiden, NetherlandsEinthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, NetherlandsDepartment of Immunology, Leiden University Medical Center, Leiden, NetherlandsDepartment of Cardiology, Leiden University Medical Center, Leiden, NetherlandsDepartment of Surgery, Leiden University Medical Center, Leiden, NetherlandsEinthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, NetherlandsDepartment of Surgery, Leiden University Medical Center, Leiden, NetherlandsEinthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, NetherlandsBackground: 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.https://www.frontiersin.org/articles/10.3389/fcvm.2020.604821/fullcardiovascular diseaseatherosclerosisinflammationPCAFregulatory T cell |
| spellingShingle | Alwin de Jong Alwin de Jong Rob C. M. de Jong Erna A. Peters Erna A. Peters Ramon Arens J. Wouter Jukema Margreet R. de Vries Margreet R. de Vries Paul H. A. Quax Paul H. A. Quax P300/CBP Associated Factor (PCAF) Deficiency Enhances Diet-Induced Atherosclerosis in ApoE3*Leiden Mice via Systemic Inhibition of Regulatory T Cells Frontiers in Cardiovascular Medicine cardiovascular disease atherosclerosis inflammation PCAF regulatory T cell |
| 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 disease atherosclerosis inflammation PCAF regulatory T cell |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2020.604821/full |
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