Clinical Significance of Pro-B-Type Natriuretic Peptide Glycosylation and Processing

Abstract

Since the principal discovery of the cardiac natriuretic peptide hormones about 25 years ago, a large amount of research has identified 2 peptides derived from pro-B-type natriuretic peptide (proBNP),1 BNP and N-terminal-proBNP (NT-proBNP), as useful plasma markers in cases of heart failure (HF) and other cardiac diseases. Our present understanding of proBNP processing and the structural biochemistry and metabolism of circulating proBNP-derived peptides, by contrast, are still far from complete. In particular, posttranslational maturation and metabolism are still poorly characterized. In this issue of Clinical Chemistry , Semenov et al. describe important results that may substantially improve our current understanding of the regulation of proBNP processing (1). Like many other hormones, BNP is derived from a prohormone. The precursor proBNP hormone is encoded by a separate gene, NPPB (natriuretic peptide precursor B), which has been assigned to chromosome 1 in humans. Its transcription has been shown to be regulated by cardiac-specific gene regulators, such as GATA, the muscle-CAT binding site, and activating protein 1/cyclic adenosine monophosphate response element-like elements (2). These cis elements have since been found to be the molecular targets of many different clinically relevant stimuli that lead to basal and inducible regulation of the NPPB gene. Transcription of the human NPPB gene can be activated through various proinflammatory and hypertrophic stimuli, such as mechanical stretch, ischemic injury/hypoxia, endothelin-1, angiotensin II, interleukins, and adrenergic agonists (2). The 5′ flanking region of the NPPB gene contains acute-phase regulatory elements, and the expression of this gene is induced with the rapid kinetics of an early- response gene. In contrast to A-type natriuretic peptide (ANP), it is believed that most BNP regulation is carried out during gene expression, with most BNP being synthesized in bursts of activation from physiological and pathophysiological stimuli, when peptide secretion occurs. Only limited amounts of …