Relevance of Molecular Forms of Brain Natriuretic Peptide for Natriuretic Peptide Research

Abstract

The focus on brain natriuretic peptide (BNP) as a biomarker, the elevation of which is associated with adverse outcomes in persons with heart failure, has obscured recognition of the myriad beneficial and compensatory biological actions provided by this small peptide hormone. Both atrial and ventricular cardiomyocytes synthesize and release both atrial natriuretic peptide (ANP) and BNP in response to volume or pressure overload, most specifically, an increase in myocardial transmural distending pressure. These peptide hormones activate the natriuretic peptide receptor type A, which contains a guanylate–cyclase domain, and this leads to the production of cGMP and the activation of downstream signaling cascades. The resulting biological actions in target tissue include the following actions that are universally beneficial in the setting of hypertension, hypertensive heart disease, and heart failure: venous and arterial vasodilation, maintenance of appropriate intravascular volume by promoting natriuresis, opposing activation of the renin–angiotensin–aldosterone system, reduced secretion of endothelin, and attenuation of central and peripheral sympathetic activity.1 In addition, the natriuretic peptide system (NPS) functions as an autocrine/paracrine system that opposes the development of cardiac fibrosis and hypertrophy via pressure-independent mechanisms.2 BNP is produced as prohormone that undergoes further processing (Figure). After removal of the 26 amino acid signal peptide from the prepro-BNP molecule, pro-BNP (1-108) is secreted from cardiomyocytes and interacts with an enzyme called corin, a transmembrane serine protease produced in cardiomyocytes, resulting in the production of a 76 amino acid amino terminal fragment (NT-BNP 1-76) and the biologically active 32 amino acid carboxyl fragment (BNP 77-108 or BNP-32).3 It is believed that the site of natriuretic peptide processing is the extracellular region of cardiomyocytes and possibly cardiac fibroblasts. Although corin appears to be unique in this capacity, other yet undiscovered enzymes may contribute to natriuretic peptide processing. BNP processing. BNP is produced as …