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Review
. 2022 Jul 6;11(7):1017.
doi: 10.3390/biology11071017.

Roles of Natriuretic Peptides and the Significance of Neprilysin in Cardiovascular Diseases

Hitoshi Nakagawa  1 , Yoshihiko Saito  2
Affiliations
Review

Roles of Natriuretic Peptides and the Significance of Neprilysin in Cardiovascular Diseases

Hitoshi Nakagawa et al. Biology (Basel). .

Abstract

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) activate the guanylyl cyclase A receptor (GC-A), which synthesizes the second messenger cGMP in a wide variety of tissues and cells. C-type natriuretic peptide (CNP) activates the cGMP-producing guanylyl cyclase B receptor (GC-B) in chondrocytes, endothelial cells, and possibly smooth muscle cells, cardiomyocytes, and cardiac fibroblasts. The development of genetically modified mice has helped elucidate the physiological roles of natriuretic peptides via GC-A or GC-B. These include the hormonal effects of ANP/BNP in the vasculature, autocrine effects of ANP/BNP in cardiomyocytes, and paracrine effects of CNP in the vasculature and cardiomyocytes. Neprilysin (NEP) is a transmembrane neutral endopeptidase that degrades the three natriuretic peptides. Recently, mice overexpressing NEP, specifically in cardiomyocytes, revealed that local cardiac NEP plays a vital role in regulating natriuretic peptides in the heart tissue. Since NEP inhibition is a clinically accepted approach for heart failure treatment, the physiological roles of natriuretic peptides have regained attention. This article focuses on the physiological roles of natriuretic peptides elucidated in mice with GC-A or GC-B deletion, the significance of NEP in natriuretic peptide metabolism, and the long-term effects of angiotensin receptor-neprilysin inhibitor (ARNI) on cardiovascular diseases.

Keywords: cardiac remodeling; heart failure; natriuretic peptide; neprilysin.

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Conflict of interest statement

The authors declare no conflict of interest. Saito Y. has received research funds from Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Novartis Pharma K.K.

Figures

Figure 1
Figure 1
Protective autocrine effects of natriuretic peptides against adverse cardiac remodeling in cardiomyocytes. Natriuretic peptides/GC-A signaling phosphorylates regulator of G-protein signaling subtype 4 (RGS4), resulting in the inhibition of Gαq signaling coupled with Ang II type 1A receptor [33,34], inhibits the activation of transient receptor potential C6 (TRPC6) [35] and attenuates the genomic actions of the cardiac mineralocorticoid receptor (MR) in cardiomyocytes [37].
Figure 2
Figure 2
The effect of NEP on cardiomyocytes and the potential role of ARNI. Orally administered ARNI may directly affect the heart and lead to reverse remodeling by increasing cGMP signaling, even at high concentrations of cardiac natriuretic peptides [61]. LBQ657, sacubitrilat (the active metabolite of sacubitril).
See this image and copyright information in PMC

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Grants and funding

This work was partly supported by the grants-in-Aid Program from the Ministry of Health: Labour and Welfare of Japan and by JSPS. KAKENHI grant number 22K08192.

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