HDAC1 Mediates High Salt‐Induced α‐Adrenergic Sensitivity in Mouse Aorta

Abstract

Clincal studies have shown that high salt intake can have a negative impact on vascular function and induce hypertension in some individuals; however, the mechanism for these effects is not well understood. We previously found that histone deacetylase 1 (HDAC1) is upregulated in response to a high salt diet and have reported that HDAC1 deacetylates endothelial nitric oxide synthase (NOS3) leading to reduced NO production. Adrenergic vasoconstriction may be enhanced by the loss of NO. We therefore hypothesized that high salt induces enhanced adrenergic vasoconstriction via HDAC1. In order to test this, we isolated aortic segments from both male and female mice after 1 week of either normal salt diet (NS; 0.49% NaCl) or high salt diet (HS; 4% NaCl). Aortic constriction was measured in response to 31.62 μM phenylephrine, an α1‐adrenergic receptor agonist, in the presence of vehicle or 300 nM MS‐275, an HDAC1 inhibitor, pre‐incubated for 40 min. Aorta from mice on HS displayed greater constriction in response to phenylephrine compared to aorta from mice on NS (HS: 13.16 ± 0.61 mN vs. NS: 8.01 ± 0.51 mN, n=3–5, p<0.001). MS‐275 pre‐treatment did not change PE‐induced vasoconstriction in aorta from mice on NS (Veh: 8.01 ± 0.51 mN vs. MS‐275: 7.04 ± 2.42 mN, n=2–3). While MS‐275 pre‐treatment reduced PE‐induced vasoconstriction in aorta from mice on HS (Veh: 13.16 ± 0.61 mN vs. MS‐275: 10.78 ± 0.73 mN, n=3–5, p<0.05). HS and NS had similar vasoconstriction induced by 60 mM KCl (NS: 4.85 ± 0.69 mN vs. HS: 5.29 ± 0.83 mN, n=3–5). These data suggest that HS induces enhanced adrenergic vasoconstriction via an HDAC1‐dependent mechanism. Because, adrenergic vasoconstriction may be enhanced by the loss of NO and/or increased reactive oxygen species (ROS), we hypothesized that HDAC1 leads to NOS3 uncoupling, reducing NO and increasing ROS. Endothelial cells were transfected with HDAC1 plasmid and Western blot confirmed HDAC1 over‐expression. Basal and stimulated ROS production was detected by luminol luminescence. HDAC1 overexpression increased both basal NOS dependent ROS production (Vector: 66.35 ± 4.91 RLU/sec/g vs. HDAC1: 111.46 ± 11.98 RLU/sec/g, n=3, p<0.05) and stimulated NOS dependent ROS production (Vector: 856.38 ± 196.10 RLU/sec/g vs. HDAC1: 1578.93 ± 29.59 RLU/sec/g, n=3, p<0.05). These data suggest that HDAC1 deacetylation of NOS3 results in NOS‐dependent ROS. Taken together, these findings suggest that HDAC1 contributes indirectly to the enhanced adrenergic mediated signaling observed in high salt fed animals through the uncoupling of NOS3.Support or Funding InformationThis research was funded by Translational and Molecular Sciences (TMS) Training Grant 5 T32 GM 109780‐3 awarded to Luke Dunaway, KO1‐DK‐105038 awarded to Dr. Kelly A. Hyndman, and HL 136936 awarded to Dr. Jennifer S. Pollock and Dr. David M. Pollock.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.