Natriuretic Peptides as Biomarkers: Narrative Review andConsiderations in Cardiovascular and Respiratory Dysfunctions

Figures

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  Figure 1. ANP and BNP synthesis in human cardiomyocytes. A) ProANP (126 aa) is cleaved into the 28 amino-acid active ANP and the 98 amino-acid NT-proANP by the enzymes corin and furin. Human preproANP is 151 amino acids in length. Cleavage of the amino-terminal signal sequence results in the 126-amino-acid proANP, the predominant form stored in atrial granules [22]. ANP is primarily expressed and stored in granules in the atria, although it is present at lower concentrations in tissues such as the ventricles and kidneys. B) BNP is synthesized in various organs but primarily in the left ventricular myocardium following mechanical stretching caused by volume overload [23]. PreproBNP (134 aa) is first cleaved in the sarcoplasmic reticulum to pre-pro (26-amino-acid signaling peptide) and the proBNP (108 aa). ProBNP is then cleaved by convertase enzymes (corin and furin) into the biologically active BNP NT-proBNP (an inactive signal peptide), being both released into the blood [10,23].

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  Figure 2. Natriuretic Peptide Receptors A, B, and C. NPR-A and NPR-B have a similar structure and are linked to the cGMP-dependent signaling cascade. NPR-C does not possess a GC domain and has no direct effect on cGMP levels [35-37]. Although the extracellular domain of NPR-C is 30% identical to NPR-A and NPR-B, it is not coupled to GC. Affinity to NPR-A: ANP ≥ BNP >>> CNP [12]. Affinity to NPR-B: CNP >> ANP ≥ BNP. Affinity to NPR-C is controversial: ANP≥CNP≥BNP; ANP=CNP=BNP; ANP=CNP>BNP [12,36,38-41]. Although there are controversies regarding the peptides’ affinity to NPR-C, it is assumed that ANP has the highest and BNP has the lowest affinity for NPR-C [36,38-41]. Hypothesis for NPR-C and investigations/development of selective agonists are under course. It might involve inhibitory (Gi) and/or stimulatory protein (Gq) activation, as well as activation of e-NOS leading to NO production. GC: Guanylyl Cyclase. cGMP: cyclic Guanosine Monophosphate. AC: Adenylyl Cyclase. e-NOS: endothelial Nitric Oxide Synthase. NO: Nitric Oxide.