Reciprocal regulation of human soluble and particulate guanylate cyclases <i>in vivo</i>

Madhani, Melanie; Okorie, M; Hobbs, Adrian J.; MacAllister, Raymond J.

doi:10.1038/sj.bjp.0706920

Cited by 28 publications

(22 citation statements)

References 37 publications

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“…Effect of NO on sGC Promoter Activity in HASMCs-To assess the effect of the sGC ligand NO on expression of the enzyme in HASMCs (to establish the existence of a feedback loop in terms of enzyme expression, which is well established to occur biochemically (30,40)), human ␣ 1 and ␤ 1 sGC promoter activity was examined in the presence of the NO donor DETA-NONOate (releases NO spontaneously in aqueous solution (41)). Pilot studies revealed that for the ␣ 1 subunit, the promoter activity was inhibited to the greatest extent in the A0.3 construct, suggesting that key NO-dependent repressors are located in this region of the promoter.…”

Section: Resultsmentioning

confidence: 99%

Characterization of the Human α1β1 Soluble Guanylyl Cyclase Promoter

Marro

Peiró

Panayiotou

et al. 2008

Journal of Biological Chemistry

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Soluble guanylyl cyclase (sGC) is the principal receptor for NO and plays a ubiquitous role in regulating cellular function. This is exemplified in the cardiovascular system where sGC governs smooth muscle tone and growth, vascular permeability, leukocyte flux, and platelet aggregation. As a consequence, aberrant NO-sGC signaling has been linked to diseases including hypertension, atherosclerosis, and stroke. Despite these key (patho)physiological roles, little is known about the expressional regulation of sGC. To address this deficit, we have characterized the promoter activity of human ␣ 1 and ␤ 1 sGC genes in a cell type relevant to cardiovascular (patho)physiology, primary human aortic smooth muscle cells. Luciferase reporter constructs revealed that the 0.3-and 0.5-kb regions upstream of the transcription start sites were optimal for ␣ 1 and ␤ 1 sGC promoter activity, respectively. Deletion of consensus sites for c-Myb, GAGA, NFAT, NF-B(p50), and CCAAT-binding factor(s) (CCAAT-BF) revealed that these are the principal transcription factors regulating basal sGC expression. In addition, under pro-inflammatory conditions, the effects of the strongest ␣ 1 and ␤ 1 sGC repressors were enhanced, and enzyme expression and activity were reduced; in particular, NF-B(p50) is pivotal in regulating enzyme expression under such conditions. NO itself also elicited a cGMP-independent negative feedback effect on sGC promoter activity that is mediated, in part, via CCAAT-BF activity. In sum, these data provide a systematic characterization of the promoter activity of human sGC ␣ 1 and ␤ 1 subunits and identify key transcription factors that govern subunit expression under basal and pro-inflammatory (i.e. atherogenic) conditions and in the presence of ligand NO.

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Section: Resultsmentioning

confidence: 99%

Characterization of the Human α1β1 Soluble Guanylyl Cyclase Promoter

Marro

Peiró

Panayiotou

et al. 2008

Journal of Biological Chemistry

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“…In one canine study [73], tolerance was not observed following chronic administration of BNP. Further studies are needed in this area, as interactions between the NO and the NP systems have been observed [21,76] and tolerance is a recognized phenomenon with the former [77].…”

Section: Novel Routes Of Administrationmentioning

confidence: 97%

Natriuretic peptides and therapeutic applications

2007

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Since the discovery of atrial natriuretic factor by de Bold et al., there has been tremendous progress in our understanding of the physiologic, diagnostic and therapeutic roles of the natriuretic peptides (NPs) in health and disease. Natriuretic peptides are endogenous hormones that are released by the heart in response to myocardial stretch and overload. Three mammalian NPs have been identified and characterized, including atrial natriuretic peptide (ANP or atrial natriuretic factor), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). In addition, Dendroaspis natriuretic peptide (DNP) has been isolated from the venom of Dendroaspis angusticeps (the green mamba snake), and urodilatin from human urine. These peptides are structurally similar and they consist of a 17-amino-acid core ring and a cysteine bridge. Both ANP and BNP bind to natriuretic peptide receptor A (NPR-A) that are expressed in the heart and other organs. Activation of NPR-A generates an increase in cyclic guanosine monophosphate, which mediates natriuresis, inhibition of renin and aldosterone, as well as vasorelaxant, anti-fibrotic, anti-hypertrophic, and lusitropic effects. The NP system thus serves as an important compensatory mechanism against neurohumoral activation in heart failure. This provides a strong rationale for the use of exogenous NPs in the management of acutely decompensated heart failure. In this article, the therapeutic applications of NPs in the acute heart failure syndromes are reviewed. Emerging therapeutic agents and areas for future research are discussed.

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“…30 Importantly, activation of sGC has been shown to be reciprocally regulated with GC-A, that is, activation of one inhibits activation of the other. 31,32 Thus, eNOS activation by TRV120027 may indirectly reduce activation of GC-A with corresponding reductions in plasma cGMP.…”

Section: Discussionmentioning

confidence: 99%

Cardiorenal Actions of TRV120027, a Novel ß-Arrestin–Biased Ligand at the Angiotensin II Type I Receptor, in Healthy and Heart Failure Canines

Boerrigter

Lark

Whalen

et al. 2011

Circ: Heart Failure

151

105

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Background-The angiotensin II type 1 receptor (AT1R) plays a key role in regulating cardiorenal function. Classic "unbiased" AT1R antagonists block receptor coupling to both G ␣q and ß-arrestin-mediated signals, which desensitize G-protein signaling as well as transduce G-protein-independent signals. TRV120027 is a novel ß-arrestin-biased AT1R ligand, which engages ß-arrestins while blocking G-protein signaling. At the AT1R, TRV120027 can inhibit angiotensin II-mediated vasoconstriction, whereas, through ß-arrestin coupling, increase cardiomyocyte contractility. We defined for the first time the acute cardiorenal actions of TRV120027 in healthy and heart failure (HF) canines. Methods and Results-Healthy and HF canines (induced by tachypacing) were anesthetized. After instrumentation and equilibration, a 30-minute baseline clearance was performed, followed by further clearance with escalating doses of intravenous TRV120027 (0.01, 0.1, 1, 10, and 100 g/kg per minute) and a 30-minute washout. In healthy canines, TRV120027 decreased pulmonary capillary wedge pressure and systemic and renal vascular resistances, while increasing cardiac output, renal blood flow, glomerular filtration rate, and urinary sodium excretion. In HF canines, TRV120027 decreased mean arterial pressure, right atrial pressure, and pulmonary capillary wedge pressure, systemic and renal vascular resistances and increased cardiac output and renal blood flow. Glomerular filtration rate and urinary sodium excretion were maintained. Conclusions-We report for the first time the cardiorenal actions of the novel ß-arrestin-biased AT1R ligand TRV120027.In both normal and HF canines, TRV120027 demonstrated cardiac unloading actions while preserving renal function. With this beneficial pharmacological profile, TRV120027 represents a novel strategy for the treatment of HF. (Circ Heart Fail. 2011;4:770-778.)

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Reciprocal regulation of human soluble and particulate guanylate cyclases in vivo

Cited by 28 publications

References 37 publications

Characterization of the Human α1β1 Soluble Guanylyl Cyclase Promoter

Characterization of the Human α1β1 Soluble Guanylyl Cyclase Promoter

Natriuretic peptides and therapeutic applications

Cardiorenal Actions of TRV120027, a Novel ß-Arrestin–Biased Ligand at the Angiotensin II Type I Receptor, in Healthy and Heart Failure Canines

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