High Sodium Induces IsoLG-Adducted Histones and Epigenetic Modifications in Myeloid Immune Cells

Background: Salt-sensitivity of blood pressure (SSBP) puts both normotensive and hypertensive individuals at a higher risk for cardiovascular morbidity and mortality. Environmental and dietary factors, such as oxidative stress and salt, induce epigenetic regulation changes in the development of SSBP. Isolevuglandins (IsoLGs) are increased in multiple oxidative-stress-associated diseases, including SSBP. IsoLGs adduct histones, specifically H3 and H4 histone proteins. However, the impact of IsoLG-modified histones on gene transcription remains unclear. We hypothesized that elevated sodium in myeloid cells leads to IsoLG-adducted histones, thereby epigenetically contributing to salt-sensitive hypertension. Methods: RNA sequencing analysis was performed on I solated monocytes from 11 hypertensive individuals cultured in either normal sodium (150mM) or high sodium (190mM). In vivo studies were performed on 19 hypertensive subject enrolled in an acute inpatient protocol to assess response to salt loading (460 mmoL/24 hours) and salt depletion (10 mmoL/24 hours, and furosemide 40 mg x 3). IsoLG-containing dendritic cells (DCs) were identified using flow cytometry as CD45 + MerTK - HLADR + CD1c + . Isolated PBMCs from a salt-sensitive subject (ΔSBP SD-SL = -12.9) and a salt-resistant subject (ΔSBP SD-SL = 0.35) were analyzed using an assay for transposase-accessible chromatin with high-throughput sequencing (ATACseq). Histones were isolated from splenic MHC-II + cells treated in vitro with either normal or high sodium media and Western blotted for IsoLGs using a selective ScFv (D11). Results: Utilizing the bulk RNA sequencing of isolated monocytes, combined with the EpiFactors database, we identified differentially expressed genes related to histones and their modifications. High sodium exposure resulted in an overall upregulation of histone modifications, notably HIST4H4 (25.4 ± 4.6 vs. 65.5 ± 6.5; n=11, q=1.5 x 10 -3 , FDR < 0.05). IsoLG-containing DCs during the salt sensitivity protocol correlated with ∆SBP (R 2 =0.25, p=0.03). ATAC-seq data revealed differential chromatin accessibility and distinct motif enrichment in cDC2 and CD14 + monocyte clusters, highlighting significant epigenetic changes between salt-sensitive and salt-resistant individuals in response to salt status. Additionally, IsoLG-adducted histones and histone H4 expression levels increased in response to high sodium environments compared to normal sodium. Conclusions: Our results suggest the high sodium environment increase in IsoLG-adducts and chromatin accessibility may epigenetically regulate innate immune cells in SSBP. Funding: NIH-R01HL147818, This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.