No abstract

No abstract

The two vasoactive hormones, angiotensin II (ANG II; vasoconstrictive) and atrial natriuretic peptide (ANP; vasodilatory) antagonize the biological actions of each other. ANP acting through natriuretic peptide receptor-A (NPRA) lowers blood pressure and blood volume. We tested hypothesis that ANG ii plays critical roles in the transcriptional repression of Npr1 (encoding NPRA) and receptor function. ANG II significantly decreased NPRA mRNA and protein levels and cGMP accumulation in cultured mesangial cells and attenuated Anp-mediated relaxation of aortic rings ex vivo. the transcription factors, cAMP-response element-binding protein (CREB) and heat-shock factor-4a (HSF-4a) facilitated the ANG II-mediated repressive effects on Npr1 transcription. Tyrosine kinase (TK) inhibitor, genistein and phosphatidylinositol 3-kinase (PI-3K) inhibitor, wortmannin reversed the ANG II-dependent repression of Npr1 transcription and receptor function. ANG II enhanced the activities of Class I histone deacetylases (HDACs 1/2), thereby decreased histone acetylation of H3K9/14ac and H4K8ac. The repressive effect of ANG II on Npr1 transcription and receptor signaling seems to be transduced by tK and PI-3K pathways and modulated by CREB, HSF-4a, HDACs, and modified histones. The current findings suggest that ANG II-mediated repressive mechanisms of Npr1 transcription and receptor function may provide new molecular targets for treatment and prevention of hypertension and cardiovascular diseases.Atrial and brain natriuretic peptides (ANP and BNP) are endogenous cardiac hormones that regulate sodium excretion, water balance, and steroidogenesis, processes that are all largely directed toward reducing blood pressure and blood volume 1-4 . Both ANP and BNP are primarily synthesized in atrial myocytes and to a much lesser extent, they are synthesized in ventricular cells and stored in dense granules 1,5 . A third peptide, C-type natriuretic peptide (CNP), which is highly homologous to ANP and BNP, is predominantly present in the endothelial cells and the central nervous system 6 . ANP and BNP exhibit their major effects in diverse organ systems, including kidneys, adrenal glands, heart, vasculature, gonads, and adipose tissues 2,7-12 . The early discovery of three related natriuretic peptides (NPs) hormones, prompted the cloning and characterization of three distinct subtypes of natriuretic peptide receptors (NPRs). These NP receptors included: natriuretic peptide receptor-A (NPRA), receptor-B (NPRB), and receptor-C (NPRC), with binding characteristics of ANP and BNP to NPRA, CNP to NPRB, and all three NPs (ANP, BNP, and CNP) to NPRC 13-17 . NPRA and NPRB, both of which contain a guanylyl cyclase (GC) domain, are also referred to, respectively, as GC-A/NPRA and GC-B/NPRB. The NPRA has generally been considered to be the primary receptor of ANP and BNP, the reason being that most of the physiological effects of these hormones are triggered by rapidly activating this receptor and the generation of its intracellular second messenger cGMP 15,[1...

Atrial natriuretic peptide (ANP) exerts its biological effects by binding to guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), which generates the second messenger cGMP. The molecular mechanism mediating Npr1 (coding for GC-A/NPRA) gene regulation and expression is not well understood. The objective of this study was to elucidate the mechanism by which Ets-1 contributes towards the regulation of Npr1 gene transcription and expression. Chromatin immunoprecipitation and gel shift assays confirmed the in vivo and in vitro binding of Ets-1 to Npr1 promoter. Overexpression of Ets-1 significantly enhanced NPRA mRNA levels, protein expression, guanylyl cyclase (GC) activity, and ANP-stimulated intracellular accumulation of cGMP levels in transfected cells. Depletion of endogenous Ets-1 by small interfering RNA (siRNA) dramatically decreased promoter activity by 80%. Moreover, methylation of the Npr1 promoter region −356 to +55 significantly reduced the promoter activity and hypermethylation around the Ets-1 binding sites directly reduced the Ets-1 binding to Npr1 promoter. Collectively, our present results demonstrate that the Npr1 gene transcription and GC activity of the receptor are critically controlled by Ets-1 in target cells.

No abstract