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

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.

Transferrin-Conjugated Melittin-Loaded L-Arginine-Coated Iron Oxide Nanoparticles for Mitigating Beta-Amyloid Pathology of the 5XFAD Mouse Brain

“…ACE1, positioned at the N-terminus of the Aβ peptide, degrades residues 16 and 17 [53], while ACE2 targets residues 7, 16, and 17 [54]. IDE exhibits degradation activity toward residues 4 and 8, while neprilysin acts upon positions 16-17, akin to ACE1 [55,56]. In addition, matrix metalloproteinases have also been implicated in Aβ degradation [57].…”

Effect of sacubitril/valsartan on brain natriuretic peptide level and prognosis of acute cerebral infarction

“…This difference in substrate specificity can be attributed to their structural differences: Due to the short amino- and carboxy-terminal tails of ANP and the lack of carboxy-terminal tails of CNP lead to more efficient geometric interactions with the catalytic site and subsequent cleavage. In contrast, the long tails of BNP do not allow its ring to form appropriate substrate sites for catalysis, resulting in initial cleavage occurring outside the ring structure [ 33 ]. Ibrahim et al [ 34 ] found that ANP concentrations were consistently and substantially increased after treatment with sacubitril/valsartan, while BNP concentrations differed across measurements, and CNP circulating concentrations were lower and unaffected by NEP inhibition.…”