Abstract
Background: Diabetic patients are characterized by a systemic pro-inflammatory state and an increased propensity to develop atherosclerosis. Since epigenetic mechanisms are known to be involved in the regulation of inflammatory genes of vascular cells under diabetic conditions, we hypothesized that uncontrolled hyperglycemia may epigenetically skew circulating CD34+ progenitors towards an inflammatory phenotype. Results: We investigated the impact of hyperglycemia on the epigenetic makeup of NFkB gene, a gate-keeper of the inflammatory control of CD34+ cells, and on the differentiation into myeloid progenitors. CD34+ cells exposed to high glucose (HG) showed a significant reduction of the repressive epigenetic modification H3K9me3 on RELA/p65 gene encoding for nuclear factor NF-kappa-B p65 subunit. This epigenetic alteration coincided with an increased recruitment of RNA polymerase II at level of p65 promoter and with a significant transcription up-regulation. Interestingly, the KAT2B/PCAF gene, an histone acetyltransferase implicated in NFkB-p65 acetylation and nuclear stabilization, was also overexpressed. Consistently, HG-CD34+ cells showed higher acetylation of NFkB in the lysine-310 and increased expression and secretion of the NFkB-p65 target cytokines, TNFα and IL6. Moreover, in vitro differentiation of HG-CD34+ cells into myeloid lineage generated higher level of pro-inflammatory CD16+ and CD14+ CD16+ monocyte subsets when compared to the normoglycemic counterpart. Conclusions: These results suggest that elevated glucose exposure might epigenetically prime CD34+ cells for a pro-inflammatory response as well as skew CD34+ cell differentiation into inflammatory cell lineages. Disclosure M. Vinci: None. V. Vigorelli: None. S. Genovese: Advisory Panel; Self; Novartis Pharmaceuticals Corporation, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Hikma Pharmaceuticals. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Takeda Pharmaceutical Company Limited. G. Pompilio: None. Funding Ricerca Finalizzata, Ministero della Salute (PE-2011-02348537)
Published Version
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