ArticleHuman cell2026
Histone H4K5 deacetylation by enhanced HDAC1 expression drives endothelial inflammation in diabetes through repression of the KLF2-eNOS axis.
Article in Human cell, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Endothelial dysfunction is a hallmark of diabetes, primarily driven by fluctuating blood glucose levels that contribute to vascular complications. Epigenetic regulation through histone modifications plays a crucial role in mediating such pathological gene expression changes. This study delineates the differential acetylation pattern of histone H4 lysine residues in endothelial cells exposed to intermittent high glucose (IHG) conditions. IHG treatment led to a significant deacetylation of H4K5 and H4K16 residues, whereas acetylation at H4K8 and H4K12 remained unaltered. Consistently, streptozotocin (STZ)-induced diabetic rats exhibited reduced H4K5 acetylation specifically in the glomerular endothelium after six weeks of hyperglycemia. Mechanistically, human umbilical vein endothelial cells (HUVECs), human glomerular endothelial cells (HGECs) and EA.hy926 cells demonstrated a marked upregulation of histone deacetylase 1 (HDAC1) under IHG conditions, which was corroborated by elevated expression of ICAM1, p21 and reduced eNOS and KLF2. Furthermore, we also observed an increased HDAC1 expression in diabetic rat glomeruli. Among histone acetyl transferases (HATs) specific to H4K5Ac, KAT7, KAT6A, and p300 were elevated, while PCAF showed a reduction under IHG stress. Furthermore, chromatin immunoprecipitation (ChIP)-qPCR analysis revealed a loss of H4K5 acetylation enrichment on the promoters of KLF2 and eNOS under IHG. Notably, pharmacological inhibition of HDAC1 with pyroxamide or gene silencing via siRNA restored H4K5 acetylation levels. Functionally, IHG exposure suppressed endothelial nitric oxide synthase (eNOS) and its transcriptional regulator KLF2, whereas HDAC1 inhibition reinstated their expression, suggesting epigenetic restoration of endothelial homeostasis. We also observed a reversal in the ICAM1 expression upon pyroxamide treatment, which was functionally characterized by the reduced THP1 cell binding to HUVEC exposed to IHG along with pyroxamide. Collectively, our findings uncover a previously unrecognized histone H4-driven mechanism governing endothelial dysfunction in diabetes, wherein HDAC1-mediated H4K5 deacetylation represses KLF2-eNOS signaling. Targeting HDAC1 thus presents a promising therapeutic approach for mitigating vascular complications associated with diabetes.
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