Histone Acetyltransferase p300 and Ets‐1 Synergistically Activate Guanylyl Cyclase/Natriuretic Peptide Receptor‐A Gene Expression

Abstract

Cardiac hormone atrial natriuretic peptide (ANP) plays a pivotal role in maintaining blood pressure and cardiovascular homeostasis. Activation of guanylyl cyclase/natriuretic peptide receptor‐A (GC‐A/NPRA) by ANP produces the second messenger cGMP. The objective of the present study was to elucidate the mechanism of Npr1 (coding for GC‐A/NPRA) gene transcription and expression. The studies were carried out in cultured mouse mesangial cells (MMC) which were transiently transfected and dual luciferase activity was assayed in the cell lysate. The results showed that a 90 bp fragment (‐46 to +55) in the Npr1 promoter contains transcriptional coactivator p300 binding site. Deletion or mutation of the p300 binding site decreased the promoter activity by 50%. Chromatin immunoprecipitation assay showed in vivo binding of p300 with Npr1 promoter. Overexpression of wild‐type adenovirus E1A significantly decreased the Npr1 promoter activity by 40%, whereas the mutant E1A had no discernible effect. Moreover, p300 showed functional synergism with Ets‐1 and increased Npr1 gene transcription by almost 16‐fold, NPRA mRNA levels by 6‐fold, and ANP‐stimulated intracellular accumulation of cGMP levels by 26‐fold. The results indicate that the Npr1 gene transcription and expression are critically controlled by synergistic interaction of p300 and Ets‐1. The present findings should yield important insights into the molecular mechanisms governing Npr1 gene regulation and expression, an important locus in the control of hypertension and cardiovascular homeostasis.