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 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 heart failure in experimental dilated cardiomyopathy. Yet, patients with significant heart failure 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 heart failure. We used a well-established, dilated cardiomyopathy model to evaluate gene and protein expression as mice longitudinally developed Stages A-D heart failure. Cardiac systolic function (ejection fraction) continuously declined over time (P<0.001). Cardiac corin transcripts were decreased at early Stage B heart failure and remained low through Stages C-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 (Stage C-D) and plasma levels rose only with terminal heart failure (Stage D, P<0.001). Immunoreactive plasma ANP and BNP levels were positively associated with plasma cyclic guanosine monophosphate (cGMP) levels (r=0.82, P=0.01 & r=0.8, P=0.02 respectively). In experimental dilated cardiomyopathy, corin levels declined early with progressive systolic dysfunction before the development of heart failure, while significant increases in plasma ANP, BNP and cGMP levels were found only in later Stage (C, D) heart failure. This dyssynchrony in expression of corin vs. ANP/BNP may impair cleavage-activation of pro-natriuretic peptides and thereby promote the transition from earlier to later stage heart failure.

Global left atrial failure in heart failure

“…A failure of coordinated expression of cardiac levels of corin and the proNPs may lead to reduced activation of proNPs and functional dysregulation of the NP system in HF . This may contribute to the decreased cleavage and elevated levels of unprocessed ANPs in patients with HF, lending support to the idea that HF is a corin‐deficient state in which low corin levels may have a causative role ( Figure ) . This assumption is further supported by the findings of a recent experimental study, which showed that corin overexpression improved cardiac function, reduced pulmonary oedema, and increased survival in a mouse model of dilated cardiomyopathy .…”

“…Experimental studies have demonstrated that intravenous infusion of atrial extracts from normal rats incites a rapid and potent diuretic and vasodilating response, whereas, such a response is not observed when atrial extracts from hamsters with congestive HF are used . Moreover, lack of coordination, or dyssynchrony, has been recently shown in cardiac corin and proANP/proBNP expression with declining systolic function in an experimental mouse model of dilated cardiomyopathy . A failure of coordinated expression of cardiac levels of corin and the proNPs may lead to reduced activation of proNPs and functional dysregulation of the NP system in HF .…”

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

“…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.…”

Atrial Natriuretic Peptide ― Old But New Therapeutic in Cardiovascular Diseases ―

“…ProANP is processed into NT-proANP and ANP by the cardiac serine protease et al reported that decreased corin levels promoted the transition from the early to late stage of HF with impaired proANP processing in a dilated cardiomyopathy (DCM) model in mice. 49 When considered together, these studies suggest that corin may play a role in controlling the HT and cardiac hypertrophy that proceed to the development of HF, specifically through proANP processing. There are only a few studies suggesting possible therapeutic strategies regarding corin to facilitate proANP processing to ANP.…”