Natriuretic Peptide Signaling via Guanylyl Cyclase (GC)-A: An Endogenous Protective Mechanism of the Heart

Ichiro Kishimoto,Kenji Kangawa,Takeshi Tokudome,Takeshi Horio,Kazuwa Nakao,David Garbers

doi:10.2174/157340309787048068

Ichiro Kishimoto, Kenji Kangawa + Show 4 more

Open Access

https://doi.org/10.2174/157340309787048068

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Abstract

Atrial and brain natriuretic peptides (ANP and BNP, respectively) are cardiac hormones, secretions of which are markedly upregulated during cardiac failure, making their plasma levels clinically useful diagnostic markers. ANP and BNP exert potent diuretic, natriuretic and vasorelaxant effects, which are mediated via their common receptor, guanylyl cyclase (GC)-A (also called natriuretic peptide receptor (NPR)-A). Mice deficient for GC-A are mildly hypertensive and show marked cardiac hypertrophy and fibrosis that is disproportionately severe, given their modestly higher blood pressure. Indeed, the cardiac hypertrophy seen in these mice is enhanced in a blood pressure-independent manner and is suppressed by cardiomyocyte-specific overexpression of GC-A. These results suggest that the actions of a local cardiac ANP/BNP-GC-A system are essential for maintenance of normal cardiac architecture. In addition, GC-A was shown to exert its cardioprotective effects by inhibiting angiotensin II-induced hypertrophic signaling, and recent evidence suggests that regulator of G protein signaling (RGS) subtype 4 is involved in the GC-A-mediated inhibition of Gαq-coupled hypertrophic signal transduction. Furthermore, several different groups have reported that functional mutations in the promoter region of the human GC-A gene are associated with essential hypertension and ventricular hypertrophy. These findings suggest that endogenous GC-A protects the heart from pathological hypertrophic stimuli, and that humans who express only low levels of GC-A are genetically predisposed to cardiac remodeling and hypertension.

Highlights

Normal cardiac structure is maintained by a sophisticated set of mechanical and cellular “checks and balances”, disturbance of which leads to a process called remodeling [1]
Stimulation of AT1a by exogenous application of Ang II, at a dose that does not affect blood pressure, significantly exacerbated cardiac hypertrophy and dramatically augmented interstitial fibrosis in guanylyl cyclase (GC)-A-KO mice, but not in wild-type animals. These results suggest that cardiac hypertrophy and fibrosis in GCA-deficient mice are related, at least in part, to the enhanced cardiac AT1a signaling, and that endogenous GC-A inhibits the excessive activation of AT1a signaling
We propose that endogenous atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) exert their antihypertrophic effects by stimulating GC-A/PKG-mediated regulator of G protein signaling subtype 4 (RGS4) phosphorylation/activation, which leads RGS4 to associate with Gq, thereby increasing the GTPase activity of Gq

Summary

INTRODUCTION

Normal cardiac structure is maintained by a sophisticated set of mechanical and cellular “checks and balances”, disturbance of which leads to a process called remodeling [1]. In response to the overactivation of various neurohumoral and mechanical stimuli that occur during heart failure, both the expression and secretion of ANP and BNP are dramatically upregulated, making their plasma levels clinically useful markers for the diagnosis and assessment of cardiac failure [9, 10]. Both natriuretic peptides exert potent diuretic, natriuretic and vasorelaxant effects through activation of their common receptor, guanylyl cyclase (GC)-A [ called natriuretic peptide receptor (NPR)-A] We discuss the cardioprotective functions of endogenous ANP and BNP, focusing in particular on their local effects within the heart

In Vitro Studies Using Cultured Cardiomyocytes

CLINICAL IMPLICATIONS

Findings

CONCLUSION