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

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.