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Pro-Atrial Natriuretic Peptide: A Novel Guanylyl Cyclase-A Receptor Activator That Goes Beyond Atrial and B-Type Natriuretic Peptides.

ABSTRACT: The aim of this study was to determine if the atrial natriuretic peptide (ANP) precursor proANP is biologically active compared with ANP and B-type natriuretic peptide (BNP).ProANP is produced in the atria and processed to ANP and activates the guanylyl cyclase receptor-A (GC-A) and its second messenger, cyclic guanosine monophosphate (cGMP). ProANP is found in the human circulation, but its bioavailability is undefined.The in vivo actions of proANP compared with ANP, BNP, and placebo were investigated in normal canines (667 pmol/kg, n = 5/group). cGMP activation in human embryonic kidney 293 cells expressing GC-A or guanylyl cyclase receptor-B was also determined. ProANP processing and degradation were observed in serum from normal subjects (n = 13) and patients with heart failure (n = 14) ex vivo.ProANP had greater diuretic and natriuretic properties, with more sustained renal tubular actions, compared with ANP and BNP in vivo in normal canines, including marked renal vasodilation not observed with ANP or BNP. ProANP also resulted in greater and more prolonged cardiac unloading than ANP but much less hypotensive effects than BNP. ProANP stimulated cGMP generation by GC-A as much as ANP. ProANP was processed to ANP in serum from normal control subjects and patients with heart failure ex vivo.ProANP represents a novel activator of GC-A with enhanced diuretic, natriuretic, and renal vasodilating properties, and it may represent a key circulating natriuretic peptide in cardiorenal and blood pressure homeostasis. These results support the concepts that proANP may be a potential innovative therapeutic beyond ANP or BNP for cardiorenal diseases, including heart failure.

SUBMITTER: Ichiki T

PROVIDER: S-EPMC4568029 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Pro-Atrial Natriuretic Peptide: A Novel Guanylyl Cyclase-A Receptor Activator That Goes Beyond Atrial and B-Type Natriuretic Peptides.

Ichiki Tomoko T Huntley Brenda K BK Sangaralingham S Jeson SJ Burnett John C JC

JACC. Heart failure 20150901 9

<h4>Objectives</h4>The aim of this study was to determine if the atrial natriuretic peptide (ANP) precursor proANP is biologically active compared with ANP and B-type natriuretic peptide (BNP).<h4>Background</h4>ProANP is produced in the atria and processed to ANP and activates the guanylyl cyclase receptor-A (GC-A) and its second messenger, cyclic guanosine monophosphate (cGMP). ProANP is found in the human circulation, but its bioavailability is undefined.<h4>Methods</h4>The in vivo actions of ...[more]

PMID: 26362447

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Project description:Atrial natriuretic peptide (ANP), via its guanylyl cyclase A (GC-A) receptor and intracellular guanosine 3',5'-cyclic monophosphate production, is critically involved in the regulation of blood pressure. In patients with chronic heart failure, the plasma levels of ANP are increased, but the cardiovascular actions are severely blunted, indicating a receptor or postreceptor defect. Studies on metabolically labelled GC-A-overexpressing cells have indicated that GC-A is extensively phosphorylated, and that ANP-induced homologous desensitization of GC-A correlates with receptor dephosphorylation, a mechanism which might contribute to a loss of function in vivo. In this study, tandem MS analysis of the GC-A receptor, expressed in the human embryonic kidney cell line HEK293, revealed unambiguously that the intracellular domain of the receptor is phosphorylated at multiple residues: Ser487, Ser497, Thr500, Ser502, Ser506, Ser510 and Thr513. MS quantification based on multiple reaction monitoring demonstrated that ANP-provoked desensitization was accompanied by a complex pattern of receptor phosphorylation and dephosphorylation. The population of completely phosphorylated GC-A was diminished. However, intriguingly, the phosphorylation of GC-A at Ser487 was selectively enhanced after exposure to ANP. The functional relevance of this observation was analysed by site-directed mutagenesis. The substitution of Ser487 by glutamate (which mimics phosphorylation) blunted the activation of the GC-A receptor by ANP, but prevented further desensitization. Our data corroborate previous studies suggesting that the responsiveness of GC-A to ANP is regulated by phosphorylation. However, in addition to the dephosphorylation of the previously postulated sites (Ser497, Thr500, Ser502, Ser506, Ser510), homologous desensitization seems to involve the phosphorylation of GC-A at Ser487, a newly identified site of phosphorylation. The identification and further characterization of the specific mechanisms involved in the downregulation of GC-A responsiveness to ANP may have important pathophysiological implications.

Project description:BackgroundThe cardiac hormones atrial (ANP) and B-type natriuretic peptides (BNP) moderate arterial blood pressure and improve energy metabolism as well as insulin sensitivity via their shared cGMP-producing guanylyl cyclase-A (GC-A) receptor. Obesity is associated with impaired NP/GC-A/cGMP signaling, which possibly contributes to the development of type 2 diabetes and its cardiometabolic complications. In vitro, synthetic ANP, via GC-A, stimulates glucose-dependent insulin release from cultured pancreatic islets and β-cell proliferation. However, the relevance for systemic glucose homeostasis in vivo is not known. To dissect whether the endogenous cardiac hormones modulate the secretory function and/or proliferation of β-cells under (patho)physiological conditions in vivo, here we generated a novel genetic mouse model with selective disruption of the GC-A receptor in β-cells.MethodsMice with a floxed GC-A gene were bred to Rip-CreTG mice, thereby deleting GC-A selectively in β-cells (β GC-A KO). Weight gain, glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion were monitored in normal diet (ND)- and high-fat diet (HFD)-fed mice. β-cell size and number were measured by immunofluorescence-based islet morphometry.ResultsIn vitro, the insulinotropic and proliferative actions of ANP were abolished in islets isolated from β GC-A KO mice. Concordantly, in vivo, infusion of BNP mildly enhanced baseline plasma insulin levels and glucose-induced insulin secretion in control mice. This effect of exogenous BNP was abolished in β GC-A KO mice, corroborating the efficient inactivation of the GC-A receptor in β-cells. Despite this under physiological, ND conditions, fasted and fed insulin levels, glucose-induced insulin secretion, glucose tolerance and β-cell morphology were similar in β GC-A KO mice and control littermates. However, HFD-fed β GC-A KO animals had accelerated glucose intolerance and diminished adaptative β-cell proliferation.ConclusionsOur studies of β GC-A KO mice demonstrate that the cardiac hormones ANP and BNP do not modulate β-cell's growth and secretory functions under physiological, normal dietary conditions. However, endogenous NP/GC-A signaling improves the initial adaptative response of β-cells to HFD-induced obesity. Impaired β-cell NP/GC-A signaling in obese individuals might contribute to the development of type 2 diabetes.

Dataset Information

Pro-Atrial Natriuretic Peptide: A Novel Guanylyl Cyclase-A Receptor Activator That Goes Beyond Atrial and B-Type Natriuretic Peptides.

Publications

Pro-Atrial Natriuretic Peptide: A Novel Guanylyl Cyclase-A Receptor Activator That Goes Beyond Atrial and B-Type Natriuretic Peptides.

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