Depressed Corin Levels Indicate Early Systolic Dysfunction Before Increases of Atrial Natriuretic Peptide/B-Type Natriuretic Peptide and Heart Failure Development

Abstract

Dilated cardiomyopathy is a major cause of heart failure (HF) that affects millions. Corin cleaves and biologically activates pro-atrial natriuretic peptide (pro-ANP) and pro-B-type natriuretic peptide (pro-BNP). High corin levels reduce the development of systolic dysfunction and HF in experimental dilated cardiomyopathy. Yet, patients with significant HF unexpectedly show low corin levels with high plasma ANP/BNP levels. Therefore, we examined the relationship between cardiac corin expression, ANP/BNP levels, and the stages of HF. We used a well-established, dilated cardiomyopathy model to evaluate gene and protein expression as mice longitudinally developed Stages A-D HF. Cardiac systolic function (ejection fraction) continuously declined over time (P<0.001). Cardiac corin transcripts were decreased at early Stage B HF and remained low through Stages C and D (P<0.001). Cardiac corin levels were positively correlated with systolic function (r=0.96, P=0.003) and inversely with lung water (r=-0.92, P=0.001). In contrast, cardiac pro-ANP/BNP transcripts increased later (Stages C and D) and plasma levels rose only with terminal HF (Stage D, P<0.001). Immunoreactive plasma ANP and BNP levels were positively associated with plasma cyclic guanosine monophosphate levels (r=0.82, P=0.01 and r=0.8, P=0.02, respectively). In experimental dilated cardiomyopathy, corin levels declined early with progressive systolic dysfunction before the development of HF, whereas significant increases in plasma ANP, BNP, and cyclic guanosine monophosphate levels were found only in later stage (C and D) HF. This dyssynchrony in expression of corin versus ANP/BNP may impair cleavage activation of pro-natriuretic peptides, and thereby promote the transition from earlier to later stage HF.

Keywords: atrial natriuretic peptide; corin protein; dilated cardiomyopathy; heart failure; natriuretic peptides.

Figure 1. Progressive declines in systolic function and development of lung edema in DCM mice

(A) Changes in EF% and (B) FS% in mice with time. (C–D) Development of lung edema as assessed by lung to body weight ratio (LW/BW%) and the difference between wet and dry lung weights (n=7–14 per group); WT (green), DCM (blue). (E) Percent change (%Δ) in plasma cGMP levels (determined by ELISA) in DCM mice to WT littermates (red) (n=7–16 per group). Data represent mean±SD. *P<0.05, ***P<0.001.

Figure 2. Relationship between corin cardiac expression and systolic function

(A) Percent change (%Δ) of corin cardiac transcript levels in DCM mice to WT littermates determined by qRT-PCR analysis. (B–C–D) Linear regression analysis in DCM and WT mice showed a significant association between EF% (B), FS% (C), LW/BW% (D) and corin cardiac transcripts (arbitrary units). N=7–14 per group. (E) Representative immunofluorescence images (scale bars, 2mm) of 20 week old WT and DCM hearts with magnified views of atrium and ventricle (100 µm) from areas indicated by red and yellow boxes, respectively. (F) Bar graph showing total immunofluorescence intensity/ total myocardium area (Intensity/MA) in WT and DCM mice (n=5 per group). WT (green), DCM (blue). Data represent mean±SE. **P <0.01, ***P <0.001.

Figure 3. Changes in ANP, BNP levels during DCM progression

(A–B) Percent change (%Δ) in cardiac transcript of pro-ANP (A) and pro-BNP (B) in DCM mice to WT littermates determined by qRT-PCR analysis (mean±SE). (C) Percent changes (%Δ) in plasma ANP (red) and BNP (blue), determined by ELISA in DCM mice to WT littermates (mean±SD). (D–E) Pearson correlation between ANP/BNP plasma levels and cardiac pro-ANP or pro-BNP transcript levels (arbitrary units). (F) Linear regression analysis of LW/BW% and ANP plasma levels in all DCM and WT groups. (G–H) Linear regression analysis of cGMP plasma levels and ANP (G) or BNP (H) plasma levels in DCM and WT mouse groups. N=7–16 per group, ***P<0.001, **P<0.01, *P<0.05.