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Histone Deacetylase Inhibitors Upregulate Natriuretic Peptide Receptor‐A Gene Transcription via Histone Modifications and Sp1 Acetylation
Author(s) -
Kumar Prerna,
Neerukonda Smitha,
Nguyen Vickie,
Pandey Kailash N
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.550.10
Subject(s) - trichostatin a , histone deacetylase 2 , hdac8 , histone deacetylase 5 , npr1 , histone deacetylase , chemistry , hdac1 , histone h3 , hdac3 , hdac4 , acetylation , microbiology and biotechnology , atrial natriuretic peptide , npr2 , histone , biology , biochemistry , natriuretic peptide , endocrinology , medicine , gene , heart failure
Atrial natriuretic peptide (ANP) exerts its antihypertensive effects by binding to guanylyl cyclase/natriuretic peptide receptor‐A (GC‐A/NPRA), which generates the second messenger cGMP. The present study was aimed at understanding the epigenetic signaling governing Npr1 (coding for GC‐A/NPRA) gene transcription. The mouse mesangial cells were cultured in DMEM containing 10% FBS and ITS (insulin, transferrin, and sodium selenite), transfected using Lipofectamine‐2000, and treated with histone deacetylase (HDAC) inhibitors. Luciferase assay showed that trichostatin A (TSA, pan‐inhibitor) and mocetinostat (MGCD0103, class I inhibitor) induced Npr1 promoter activity by 8‐fold and 10‐fold, Npr1 mRNA levels by 4‐ and 5.3‐fold, and protein expression by 2.5‐ and 3‐fold, respectively. TSA and MGCD0103 inhibited HDAC activity by 25% and 50%, respectively. Furthermore, TSA and MGCD0103 enhanced acetylation and binding of H3‐K9/14, H4‐K12, and Sp1 to Npr1 promoter. Taken together, the present results demonstrate that TSA and MGCD0103 enhanced Npr1 gene expression via inhibition of HDAC1 and HDAC2 and increased histone H3, H4, and Sp1 acetylation. The present findings provide a novel regulatory mechanism for Npr1 gene transcription, an important player in the control of hypertension and cardiovascular homeostasis. This work was supported by the NIH grant (HL57531).