Epigenetic Regulation of Natriuretic Peptide Receptor‐A Gene by Cooperative Interaction of Retinoic acid and Sodium Butyrate via Histone Modifications in Vascular Smooth Muscle Cells

Abstract

Activation of guanylyl cyclase/natriuretic peptide receptor‐A (GC‐A/NPRA) by cardiac hormones atrial and brain natriuretic peptides (ANP and BNP) produces the second messenger cGMP, which plays a pivotal role in maintaining blood pressure and cardiovascular homeostasis. The objective of the present study was to gain insight into the epigenetic mechanisms involved in all‐trans retinoic acid (ATRA) and histone deacetylase (HDAC) inhibitor, sodium butyrate (NaBu)‐induced Npr1 gene (coding for GC‐A/NPRA) expression. The studies were carried out in rat thoracic aortic smooth muscle cells cultured in DMEM containing 10% FBS and treated with ATRA and NaBu for 24 h. The results showed that ATRA and NaBu induced Npr1 promoter activity by 12‐fold and mRNA levels by 5‐fold in an additive manner. Simultaneous treatment with ATRA and NaBu significantly increased the levels of histones H3K9/14ac, H4K12ac, and H3K4me3 (p<0.001). Overexpression of class I HDACs (HDAC 1 and HDAC 2) reduced Npr1 promoter activity by 50%. ATRA and NaBu inhibited HDAC activity by 50%. Moreover, ATRA and NaBu cooperatively enhanced histone acetyltransferse activity. The results demonstrate that ATRA and NaBu regulate Npr1 gene expression by modulation of histone modifications. The identification of epigenetic signaling as a regulator of Npr1 gene will have important implications in prevention of hypertension and cardiac remodeling.