Natriuretic Peptide Processing in Patients with and Without Left Ventricular Dysfunction

Abstract

This study aimed to examine the relationship between corin expression and circulating brain natriuretic peptide in patients with left ventricular (LV) dysfunction. Circulating levels of B-type natriuretic peptide (BNP) can be an indicator of LV dysfunction. The 32amino-acid BNP is cleaved by corin, a cardiac serine protease, from its108-amino-acid pro-brain natriuretic peptide (proBNP) precursor. This study included 25 patients with idiopathic dilated cardiomyopathy (DCMP) and LV dysfunction and 44 heart transplant recipients with normal LV function who underwent diagnostic left and right heart catheterization. Blood samples were used to determine the ratio of plasma proBNP/BNP levels, and LV endomyocardial biopsies were used to determine the expression of NPPB, which encode BNP and corin, respectively, by quantitative reverse transcription-polymerase chain reaction. Patients with DCMP revealed worse hemodynamic profiles and higher plasma proBNP and BNP levels than those of the transplant recipients. Myocardial NPPB expression was higher and CORIN expression was lower in the DCMP patients than in the transplant recipients. CORIN expression significantly correlated with NPPB expression (r = −0.585; P < 0.001), ejection fraction (EF; r = 0.694; P < 0.01), LV end-diastolic pressure (r = −0.373; P < 0.05), and indexed end-diastolic LV volume (r = −0.452; P < 0.001). In addition, the plasma proBNP/BNP levels inversely correlated with the CORIN expression (r = −0.362; P < 0.005). Decreased myocardial CORIN expression and the corresponding higher levels of circulating unprocessed proBNP in DCMP may partly account for the relative BNP resistance observed in patients with LV dysfunction.

Cardiac-Specific Overexpression of Catalytically Inactive Corin Reduces Edema, Contractile Dysfunction, and Death in Mice with Dilated Cardiomyopathy

“…Importantly, we found that cardiac-specific expression of catalytically active corin delays the onset of symptomatic HFrEF associated with lung edema and extends life in experimental mouse model of DCM [16,17]. In agreement with our results, corin cardiac transcript levels were upregulated in heart transplant recipients with normal left ventricular (LV) function in comparison with DCM/HFrEF patients [24]. These results suggested that preservation or restoration of cardiac corin levels might delay the progression of HFrEF.…”

“…Converging lines of evidence from clinical and translational studies have shown that genetic abnormalities and reduction in corin cardiac expression level negatively affect DCM and HFrEF outcomes. Cardiac transcripts and circulating levels of corin are depressed in patients and translational animal models with DCM and HFrEF [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]35,36,51], and are pathologically modulated in DCM before the onset of edema and other clinical signs and symptoms of HFrEF [22,23]. In a translationally relevant mouse model of DCM-HFrEF with reduced cardiac and plasma corin levels, we reported that genetic restoration of cardiac-specific catalytically active, native corin improved systolic function, reduced myocardial fibrosis, decreased edema, and prolonged survival [16,17].…”

“…A growing body of evidence in humans and experimental models suggests that corin, a cardiac transmembrane II serine protease, plays diagnostic, prognostic, and protective roles in DCM and HFrEF development [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. Cardiac corin is co-expressed with pro-atrial natriuretic peptide (pro-ANP) and localized on the cardiomyocyte surface [25,26], where it cleaves/activates secreted pro-ANP generating biologically active ANP peptides.…”

Utility of B-Type Natriuretic Peptide for Detecting Cardiac Involvement in Immunoglobulin Amyloidosis

“…Pre-pro BNP was processed into proBNP (108 amino acids) and subsequently proBNP was cleaved into NT-ProBNP (76 amino acids) and BNP (32 amino acid). 26,27) NT-proBNP and BNP share a common mechanism of clearance through the glomerulus. In patients with a normal or mildly decreased glomerular filtration rate (GFR), the molar ratio of NT-proBNP to BNP must be 1.0 or less because both peptides are cleared at about the same rate and have similar half-lives.…”

Single-Nucleotide Polymorphisms in the 3' Untranslated Region of CORIN Associated With Cardiovascular Diseases in a Chinese Han Population: A Case–Control Study

“…The significance of corin seems more important in HF. HF is associated not only with reduced plasma corin levels (16,17,24) and decreased myocardial CORIN expression (25), but also with impaired cleavage of pro-ANP (17). In mice with progressive dilated or ischemic cardiomyopathy, restoration of suppressed cardiac corin expression levels reduces myocardial fibrosis, improves contractile function, reduces alveolar edema and congestion, and attenuates heart failure (26)(27)(28)(29).…”