Angiotensin II represses Npr1 expression and receptor function by recruitment of transcription factors CREB and HSF-4a and activation of HDACs

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...

Focusing on Mechanoregulation Axis in Fibrosis: Sensing, Transduction and Effecting

“…Currently, four HDACIs have been approved by the U.S. Food and Drug Administration (FDA) for clinical use in hematologic tumors ( Qin et al, 2017 ), while HADCIs in fibrotic diseases are still being examined in preclinical studies. For example, trichostatin A, a pan HDACI, has shown benefits in multiple fibrosis models ( Lan et al, 2015 ; Wu et al, 2017 ; Yoon et al, 2019 ), and SK-7041, a class I HDAC-selective inhibitor, ameliorates fibrotic conditions in cardiac and renal mouse models ( Arise et al, 2020 ; Martinez-Moreno et al, 2020 ). Unlike other diseases in which one therapeutic target will be sufficient, fibrotic diseases sometimes require combined epigenetic therapy.…”

Epigenetic regulation in cardiovascular disease: mechanisms and advances in clinical trials

“…Therefore, the study suggests that Ang-II-mediated Npr1 transcription and receptor function inhibition may provide new molecular targets and an important theoretical basis for the treatment and prevention of hypertension. 117 In conclusion, these studies indicate that histone acetylation is closely related to cardiovascular diseases mechanism.…”

“… 115 Downregulation of SIRT3 expression and SIRT3 redox inactivation result in superoxide dismutase 2 (SOD2) inactivation, which promotes the occurrence of hypertension. 116 In addition, Arise et al 117 found that angiotensin II(Ang II) enhanced the activity of class I HDAC1/2, reduced histone acetylation of H3K9/14ac and H4K8ac, further inhibited Npr1 (encoding natriuretic peptide receptor-A) transcription, and decreased natriuretic peptide receptor-A protein and cGMP levels, thereby diminishing renal and vascular reactivity and attenuating atrial natriuretic peptide-mediated aortic ring relaxation. Therefore, the study suggests that Ang-II-mediated Npr1 transcription and receptor function inhibition may provide new molecular targets and an important theoretical basis for the treatment and prevention of hypertension.…”

Guanylyl cyclase/natriuretic peptide receptor-A: Identification, molecular characterization, and physiological genomics

“…Those studies indicated that phosphorylation at serine and threonine sites induces the desensitization of GC-coupled receptors. In fact, the activation of GC-A/NPRA could also be attenuated by agents such as certain growth factor, including epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) and pressure hormones, such as endothelin, vasopressin, and ANG II, which decrease the responsiveness of GC-A/NPRA ( Haneda et al, 1991 ; Yasunari et al, 1992 ; Potter and Garbers, 1994 ; Kumar et al, 1997 ; Pandey et al, 2000 ; Sharma et al, 2002 ; Garg and Pandey, 2003 ; Tripathi and Pandey, 2012 ; Alicic et al, 2018 ; Arise et al, 2020 ). The agonist-dependent activation of PKC by phorbol ester decreased GC catalytic activity of NPRA ( Haneda et al, 1991 ; Yasunari et al, 1992 ; Potter and Garbers, 1994 ; Kumar et al, 1997 ; Pandey, 2005 ; Kumar et al, 2017 ).…”