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

Autor:	de Jong A; Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands., de Jong RCM; Department of Hematology, Leiden University Medical Center, Leiden, Netherlands., Peters EA; Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands., Arens R; Department of Immunology, Leiden University Medical Center, Leiden, Netherlands., Jukema JW; Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands., de Vries MR; Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands., Quax PHA; Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands.
Jazyk:	angličtina
Zdroj:	Frontiers in cardiovascular medicine [Front Cardiovasc Med] 2021 Jan 15; Vol. 7, pp. 604821. Date of Electronic Publication: 2021 Jan 15 (Print Publication: 2020).
DOI:	10.3389/fcvm.2020.604821
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 de Jong, de Jong, Peters, Arens, Jukema, de Vries and Quax.)
Databáze:	MEDLINE
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