Association of Sodium Induced High Blood Pressure with Up-Regulation of Inducible Nitric Oxide Synthase (iNOS) Expression and Inhibition of Trimethylation of H3K27 on Its Promoter Region

Abstract

Nitric oxide (NO), a simple molecule, playing very diverse roles in the regulation of the cardiovascular, immunologic and nervous system, is formed from L-arginine by converting it to L-citrulline via nitric oxide synthase enzymes (NOS) including endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS). We previously reported that long term inhibition of iNOS by intravenous administration of aminogunidine (AG) led to an aggravation of hypertension induced by high sodium chloride (NaCl) loading. Also, high blood pressure induced by high NaCl loading is associated with higher NO production in SD rats. The goal of the present study was to clarify whether the change of blood pressure alter iNOS gene expression as well as epigenetic modification of iNOS gene promoter region. Up-regulation of iNOS mRNA and protein were observed in renal medullary tissue of high sodium infused rats. Furthermore, chromatin immunoprecipitation assay evidenced the inhibition of recruitment of methyltransferase enhancer of Zeste homology 2 (EZH2) to, and trimethylation of histone 3 (H3) at lysine 27 (K27) of iNOS gene promoter region. We concluded that blood pressure is a regulator of iNOS gene expression through alteration of histone covalent modification of its genomic DNA.