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.
Highlights
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[1,2,3,4]
We demonstrated the role of cAMP-response element-binding protein (CREB) and heat-shock factor-4a (HSF-4a) in angiotensin II (ANG II)-mediated repression of Npr[1] transcription, expression, and physiological functions using cultured male mouse mesangial cells (MMCs) in vitro and intact male mouse aortic rings ex vivo
Our findings provide the direct evidence in signifying the role of ANG II-response elements, CREB and HSF-4a in mediating the repressive effect of ANG II on Npr[1] transcription and functional responsiveness
Summary
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[1,2,3,4]. A recent study using Npr[3] (coding of NPRC) gene-knockout mice has indicated that NPRC, a non-guanylyl cyclase containing NP receptor prevents the progression of ANG II-dependent atrial fibrillation and remodeling[46]. This raises the possibility that the factors other than ANP/ NPRA/cGMP, might play a pivotal role in the cardiovascular protective effects involving NPRC, which needs to be further studied. We demonstrated the role of CREB and HSF-4a in ANG II-mediated repression of Npr[1] transcription, expression, and physiological functions using cultured male mouse mesangial cells (MMCs) in vitro and intact male mouse aortic rings ex vivo
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