Complexity of molecular forms of B-type natriuretic peptide in heart failure

In 1988, a Japanese group isolated B-type (or brain) natriuretic peptide (BNP) from porcine brain extracts by monitoring its relaxant effects on chick rectum.1 Since then studies in humans and rodents demonstrated that BNP is a cardiac hormone mainly expressed in the heart, where its concentration is considerably higher than in brain. BNP possesses a 17-amino acid ring structure containing two cysteine residues, which is essential for its biological activity. Mechanical stress, ischaemia, cytokines and neurohumoral factors, including angiotensin II, stimulate expression of BNP (figure 1),2 and levels of myocardial BNP mRNA and circulating BNP and N-terminal proBNP (NT-proBNP) are markedly increased in patients with congestive heart failure.2 BNP is therefore considered to function as an emergency defence against ventricular overload in disease states. Figure 1 Schematic representation of the stimulus, signal transduction, gene, mRNA, translation, glycosylation, processing and secretion of B-type natriuretic peptide (BNP) in myocytes, and the plasma molecular forms of BNP. Mechanical stress, ischaemia, cytokines and neurohumoral factors (eg, angiotensin II and endothelin-1) stimulate gene expression of BNP via signal transduction mediated by protein kinase C and mitogen-activated protein (MAP) kinase. BNP mRNA is translated in the endoplasmic reticulum, after which preproBNP is converted to proBNP by a signal peptidase. ProBNP is post-translationally O -glycosylated within the Golgi apparatus and cleaved to BNP and NT-proBNP in equimolar fashion by furin within the trans-Golgi network. They are then transferred to secretion vesicles and secreted into the circulation via a so-called constitutive secretion pathway. ProBNP is often heavily O -glycosylated in the N-terminal region, and furin cannot easily cleave O -glycosylated proBNP when Thr71 is O -glycosylated. In the plasma, BNP is degraded to BNP [3-32] by dipeptidyl peptidase IV, after which BNP [3–32] is further degraded to BNP [4–32], BNP [5–32] and other metabolites by aminopeptidases. …