Post-transcriptional modification of pro-BNP in heart failure: is glycosylation and circulating furin key for cardiovascular homeostasis?

With the discovery that the heart is an endocrine organ, we now know that the heart produces and releases hormones, including the natriuretic peptides (NPs). NPs are thought to be produced and released mainly in response to mechanical stretching, due to increased intravascular volume or under pathophysiological conditions, especially in heart failure (HF). B-type NP (BNP) molecular forms, especially BNP and NT-proBNP, are currently in widespread used as biomarkers in HF. Human BNP is produced as a 134-amino acid preproBNP which is subsequently processed to proBNP1-108 by cleavage of its signal peptide. ProBNP 1-108 is then processed into inactive NT-proBNP 1-76 and the GC-A receptor activator BNP 1-32 by proprotein convertases corin or furin. The processing of BNP molecular forms is therefore critical for its bioavailability. Critical regulators in proBNP processing have been revealed, including the proteases corin and furin and the role of glycosylation of proBNP. Corin—a cardiac transmembrane serine protease that is abundantly expressed in the heart and kidneys, with a functional soluble form that is shed into the circulation—cleaves both proANP and proBNP into active hormones. It has been reported that the levelsof soluble corin (i.e. circulating corin) differ significantly between males and females (it is higher in males) and is decreased in HF. In contrast, furin is thought to be an intracellular endoprotease, present in various organs, which processes not only proBNP, but several proproteins including proCNP, proTGF-beta 1 and proendothelin 1. Furin expression is increased in atrial myocardium in experimental HF; however, to date there have been no studies on functional circulating furin. Glycosylation plays an important role in the regulation of enzymatic cleavage. Seven O-glycosylated sites have been reported within proBNP, all in the NT-proBNP (aa 1-76) region. Tonne and colleagues reported that proBNP predominantly exists as a nonglycosylated form intracellularly, however, only glycosylated proBNP was detected in supernatant from cardiomyocytes in vitro. Additionally, they found that O-glycosylation of T71 residue in proBNP attenuates its processing into active BNP. Peng and colleagues further reported that proBNP glycosylation differed in HEK cells and cardiomyocytes, with T71 O-glycosylation being essential for proBNP processing by both corin and furin in HEK cells, but not in cardiomyocytes. Clinically, Nishikimi and colleagues studied circulating glycosylated or non-glycosylated NT-proBNP and found that circulating levels of BNP, non-glycosylated NT-proBNP, and glycosylated NT-proBNP all increased with the severity of HF, although the molar ratios remaining unchanged (BNP:non-glycosylated NT-proBNP and BNP:glycosylated NT-proBNP 1⁄4 1:2.4 and 1:9.6, respectively). Therefore, more glycosylated proBNP may be secreted into thecirculation thannon-glycosylatedproBNP,but the relationship between corin and furin and the glycosylation status of proBNP in its processing and circulating levels in HF remains unclear. In the current issue of this journal, Vodovar and colleagues focus on proBNP glycosylation and its processing by corin and furin in the circulation in human acute decompensated heart failure (ADHF), non-ADHF (dyspnea but no HF) and chronic HF (CHF). Utilizing plasma samples from patients from these groups, their findings are similar to what has previously been shown, that as the highest percentage of glycosylated BNP is present in CHF, suggesting that proBNP processing is altered more in CHF than in ADHF or non-ADHF. In contrast, the percentages of glycosylated proBNP in ADHF and non-ADHF patients were similar to each other. The significantly increased production and rapid release and processing of proBNP in ADHF may represent an attempt by the heart to rescue itself from volume overload by stimulating GC-A in kidney through the circulating BNP. Further, the authors tell us, for the first time, that furin activity—but not its concentration—is greater in ADHF