Differential expression of the pro-natriuretic peptide convertases corin and furin in experimental heart failure and atrial fibrosis

Abstract

In heart failure (HF), the cardiac hormone natriuretic peptides (NPs) atrial (ANP), B-type (BNP), and C-type (CNP) play a key role to protect cardiac remodeling. The proprotein convertases corin and furin process their respective pro-NPs into active NPs. Here we define in a canine model of HF furin and corin gene and protein expression in normal and failing left atrium (LA) or ventricle (LV) testing the hypothesis that the NP proproteins convertases production is altered in experimental HF. Experimental canine HF was produced by rapid right ventricular pacing for 10 days. NPs, furin, and corin mRNA expression were determined by quantitative RT-PCR. Protein concentration or expression was determined by immunostaining, radioimmunoassay, or Western blot. Furin and corin proteins were present in normal canine LA and LV myocardium and vasculature and in smooth muscle cells. In normal canines, expression of NPs was dominant in the atrium compared with the ventricle. In experimental early stage HF characterized with marked atrial fibrosis, ANP, BNP, and CNP mRNA, and protein concentrations were higher in HF LA but not HF LV compared with normals. In LA, corin mRNA and protein expressions in HF were lower, whereas furin mRNA and protein expressions were higher than normals. NPs and furin expressions were augmented in the atrium in experimental early stage HF and, conversely, corin mRNA and protein expressions were decreased with atrial remodeling. Selective changes of these NP convertases may have significance in the regulation of pro-NP processing and atrial remodeling in early stage HF.

Distinct Roles of N-Glycosylation at Different Sites of Corin in Cell Membrane Targeting and Ectodomain Shedding

“…In glycosidase digestion experiments, human corin was shown to contain abundant N-glycans but no detectable O-glycans or sialic acids (25). N-Glycans also have been detected in mouse, rat, and dog corin proteins (25,(27)(28)(29).…”

Involvement of corin downregulation in ionizing radiation-induced senescence of myocardial cells

“…5C and 6B), suggesting that the pro-forms of natriuretic peptides may be processed by other proteases, such as furin and dipeptidyl peptidase IV, which are expressed in HL-1 cells (11,24). Although the natriuretic peptide processing induced by IR was incomplete (Fig.…”

“…The fact that corin has been placed center-stage in the study of the progression of heart diseases highlights the importance of exploring the association between corin expression and RIHD severity and/or phenotype in cancer patients receiving radiotherapy (21). The two most intensively studied substrates of corin, ANP and BNP, are closely linked to compensatory mechanisms in failing hearts (11,21). An elevation in BNP levels has been suggested to reflect an attempt to correct a serious dysfunction of the heart (22).…”

“…Importantly, it has been shown that corin expression is downregulated during heart failure (11,21). Soluble corin is detected in human plasma, and its levels are decreased in patients with heart failure (21).…”

“…Corin has been identified as a cardiac protease that targets natriuretic peptides, proteolytically cleaving pro-atrial natriuretic peptide (ANP) and pro-brain natriuretic peptide (BNP) to produce the corresponding active hormone forms (9,10). The physiological significance of the function of corin has been demonstrated in studies using experimental animal models, where the disruption of the corin gene has been shown to cause hypertension and cardiac hypertrophy (11). Moreover, in patients with heart failure, corin variants have been demonstrated to be related to poor natriuretic peptide processing and overall clinical outcomes (12).…”