Background—: By promoting salt and water excretion, the corin and the atrial natriuretic peptide (ANP) system should help to maintain fluid balance in heart failure. Yet, the development of fluid retention despite high levels of ANP-related peptides suggests that this compensatory system is limited. Methods and Results—: Levels of circulating corin (the pro–ANP-converting enzyme) and pro-ANP were measured in hospitalized patients with heart failure, using novel immunoassays. Patients (n=14) had severe heart failure (New York Heart Association class III-IV) with a median ejection fraction of 18% and median brain natriuretic peptide levels of 1940 pg/mL. In heart failure, median plasma corin levels were 7.6-fold lower than measured in plasma from 16 normal control subjects (180 versus 1368 pg/mL, P <0.01). In contrast, in patients with heart failure, levels of plasma N-terminal ANP peptides (N-ANP and pro-ANP) levels were markedly elevated (42.0 versus 7.5 ng/mL, P <0.01). Levels of uncleaved pro-ANP, measured by novel immunoassays, were significantly higher in patients with heart failure ( P <0.01), suggesting that corin cleavage of pro-ANP was impaired. Median plasma levels of cyclic guanosine monophosphate were elevated in patients with heart failure (150.0 versus 7.6 pmol/mL, P <0.01), and plasma cyclic guanosine monophosphate levels positively correlated with the fractional amount of cleaved pro-ANP ( r _s =0.59, P <0.03) but not with levels of uncleaved pro-ANP, implying that the cellular response to ANP remained intact. Conclusions—: Taken together, these data suggest that there may be patients for whom low corin levels and impaired pro-ANP cleavage contribute to acute decompensation.

Heart failure, caused by dilated cardiomyopathy and other cardiac disorders such as hypertension, is a major public health problem with high morbidity and mortality. Corin, a cardiac enzyme that cleaves natriuretic peptides, is a promising biomarker of cardiomyopathy and heart failure, but its functional role in these processes is not understood. We evaluated the potential effects of corin in mice with a well-characterized model of dilated cardiomyopathy. Mice with dilated cardiomyopathy developed heart failure, reduced contractile function, cardiac fibrosis, and accelerated mortality in the setting of low corin expression. In wild-type mice, transgenic, cardiac-targeted, overexpression of corin enhanced cyclic guanosine monophosphate and blood pressure responses to pro-atrial natriuretic peptide, but did not affect heart size, contractility, body weights, survival, and blood pressure. In mice with dilated cardiomyopathy, corin overexpression significantly reduced the development of myocardial fibrosis ( P <0.05). Corin overexpression also enhanced heart contractile function (fractional shortening and ejection fraction; P <0.01) and it significantly reduced heart failure as assessed by lung water ( P <0.05) and alveolar congestion ( P <0.001). Consistent with these observations, corin overexpression significantly prolonged life in mice with dilated cardiomyopathy ( P <0.0001). These results provide the first experimental evidence that corin expression plays a role in cardiomyopathy by modulating myocardial fibrosis, cardiac function, heart failure, and survival.

The generation of plasmin by plasminogen (Pg) activators (PAs) is a physiologic process in animals that dissolves blood clots and promotes wound healing, blood vessel growth, and the migration of normal and cancerous cells. Pathogenic bacteria have evolved PAs [e.g., streptokinase (SK) and staphylokinase] that exploit the Pg system to infect animals. Animal PAs have a conserved ability to cleave a wide spectrum of animal Pgs, but the ability of bacterial PAs to cleave different animal Pgs is surprisingly restricted. We show that the spectrum of activity of an archetypal bacterial PA (SK) with animal Pgs can be profoundly altered by mutations that affect intermolecular complementarity at sites that participate in complex formation or substrate binding. Comparative sequence analysis of animal plasmins vs. close structural homologues (trypsin and chymotrypsin) that are not molecular targets for invading bacteria indicates that the sites in plasmin that interact with SK are preferentially targeted for mutation. Conversely, intermolecular contact sites in SKs that activate human Pg are more highly conserved than other loci in the molecule or than the same sites in other SKs that activate non-human Pgs. We propose that active modulation of intermolecular complementarity at sites of contact between SK and Pg may represent a competitive evolutionary strategy in a survival battle, whereby animals seek to evade bacterial invasion, and bacteria endeavor to invade their animal hosts.

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.

Dilated cardiomyopathy is a frequent cause of heart failure and death. Atrial natriuretic peptide (ANP) is a biomarker of dilated cardiomyopathy, but there is controversy whether ANP modulates the development of heart failure. Therefore, we examined whether ANP affects heart failure, cardiac remodeling, function, and survival in a well-characterized, transgenic model of dilated cardiomyopathy. Mice with dilated cardiomyopathy with normal ANP levels survived longer than mice with partial ANP (P<0.01) or full ANP deficiency (P<0.001). In dilated cardiomyopathy mice, ANP protected against the development of heart failure as indicated by reduced lung water, alveolar congestion, pleural effusions, etc. ANP improved systolic function and reduced cardiomegaly. Pathological cardiac remodeling was diminished in mice with normal ANP as indicated by decreased ventricular interstitial and perivascular fibrosis. Mice with dilated cardiomyopathy and normal ANP levels had better systolic function (P<0.001) than mice with dilated cardiomyopathy and ANP deficiency. Dilated cardiomyopathy was associated with diminished cardiac transcripts for NP receptors A and B in mice with normal ANP and ANP deficiency, but transcripts for NP receptor C and C-type natriuretic peptide were selectively altered in mice with dilated cardiomyopathy and ANP deficiency. Taken together, these data indicate that ANP has potent effects in experimental dilated cardiomyopathy that reduce the development of heart failure, prevent pathological remodeling, preserve systolic function, and reduce mortality. Despite the apparent overlap in physiological function between the NPs, these data suggest that the role of ANP in dilated cardiomyopathy and heart failure is not compensated physiologically by other NPs.