Corin Overexpression Improves Cardiac Function, Heart Failure, and Survival in Mice With Dilated Cardiomyopathy
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.
See Editorial Commentary, pp 284–285
Heart failure (HF) is a syndrome of abnormal salt and water retention that frequently occurs in the setting of reduced cardiac function or cardiomyopathy. HF is a leading cause of morbidity and mortality; it affects >5.7 million Americans, and ≈670 000 new cases are diagnosed each year.1 Despite improvements in treatment, HF is a progressive process and nearly half of patients die within 5 years.2 The factors that modulate HF development and progression in patients with cardiomyopathy are still poorly understood.
Corin is a potential biomarker of HF and cardiomyopathy.3–5 Polymorphisms in corin are linked to more severe hypertension.6 Corin is a transmembrane serine protease expressed by cardiomyocytes that cleaves natriuretic pro-atrial natriuretic peptide (ANP) to generate ANP; there is increasing evidence that it may also cleave pro-brain natriuretic peptide (BNP).7–14 The natriuretic peptides (NPs) play a critical role in maintaining normal salt and water balance and arterial blood pressure; they are also important diagnostic and prognostic biomarkers for patients with HF.15 ANP and BNP interact with the NP receptor-A to regulate cGMP levels, vasodilation, natriuresis, fibrosis, etc.9,16 As such the corin-NP system should protect against the development of progressive HF in patients with reduced systolic function.4
One of the most common causes of progressive HF, cardiac transplantation, and mortality is dilated cardiomyopathy (DCM).17 DCM has several genetic and environmental causes in humans and mice.17,18 One of the best characterized models of DCM in mice is caused by a phophorylation-resistant cAMP response element-binding protein (CREB) mutant transgene (DCMc).19–23 Mice with DCMc develop HF with features similar to human DCM including biventricular dilation, elevated NP levels, fibrosis, electrophysiologic abnormalities as well as progressive edema, dyspnea, hepatic congestion, and early demise.19–23
Through its positive effects on natriuresis, fibrosis, and vascular resistance, the corin-NP system should delay the progression of DCM and HF. However, we and others have found that blood levels3–5,24 and cardiac transcripts for corin25 are paradoxically reduced in patients with severe DCM. Similar to humans, mice with DCMc have reduced systolic function, enhanced cardiac fibrosis, elevated NP levels, and accelerated mortality, all in the setting of decreased cardiac corin expression. Still, the contribution of corin to HF development remains controversial and poorly understood.3–5,7,24,26–28 To examine this we genetically overexpressed corin in the hearts of mice with DCMc.
We analyzed corin-transgenic (Tg) and DCMc mice in vivo and ex vivo. Experimental details are found in the online-only Data Supplement.
Survival was analyzed by the Kaplan-Meier method. Other statistical analyses were performed using nonparametric methods (unless otherwise indicated). Differences were considered to be significant if the 2-tailed P<0.05. The number of animals (n) is indicated in the figure legends or results. Data are reported as mean+SEM.
Reduced Corin Expression in DCMc Mice
Mice with cardiac Tg expression of the CREB mutant develop a DCMc accompanied by frank HF with edema, ascites, and shortened survival.19,23 Although the promoter of the corin gene does not contain CREB binding sites,29 the DCMc mice showed reduced levels of corin transcripts (Figure 1A) and protein (Figure 1B–1D) versus wild-type (WT) littermates. DCMc mice had higher ANP (2.1-fold; P<0.05; Figure S1 in the online-only Data Supplement) and BNP transcripts (3.3-fold; P<0.01; Figure S2).
To examine whether corin expression affects the progression of HF, we produced mice that selectively overexpress corin in the heart attributable to the targeting effects of the alpha myosin heavy chain promoter. Corin-Tg mice were fertile, viable, and indistinguishable from normal mice in appearance (Figure 2A). Three corin-Tg lines were identified that displayed 1.3 to 13.5-fold increased levels of corin transcripts versus WT mice (Tg1=1.3±0.1-fold; Tg2=6.9±0.5-fold; Tg3=13.5±2.5-fold assessed by Northern blot). Corin protein was increased in the heart (Figure 2B) and blood (1.4-fold; P<0.05; n=3 each group). There was no difference between WT mice and the corin-Tg mice in survival (n=701; Figure 2C) or in ANP and BNP transcripts (not shown), thus we focused our studies on the Tg line expressing the highest corin levels. Female WT and corin-Tg littermates had similar heart weights (WT 0.16±0.02 g versus Tg 0.17±0.02 g) and body:heart weight ratios (WT 296.4±12.8 versus 300.5±22.5; n=11–17 each group; Figure 2D); male mice were also similar to each other (11–20 each group). Indeed no differences in body weight were observed in mice up to 500 to 600 days old. There were no significant differences between WT and corin-Tg mice of the same gender in baseline systolic, diastolic, or mean arterial blood pressure (Figure 2E), heart rate or fractional shortening (31.9±1.2 versus 32.4±2.3).
Enhanced Corin Activity in Corin-Tg Mice
The cleavage of pro-ANP to ANP enhances cellular generation of cGMP and lowers blood pressures. In corin-Tg mice cGMP levels were slightly higher than in WT mice (Figure 3A), but there were no significant differences in mean arterial pressure (Figure 3B) or heart rate. There was enhanced cleavage of recombinant pro-ANP by hearts from corin-Tg mice (Figure S3). Bolus injection of pro-ANP increased cGMP levels in both corin-Tg and WT mice (Figure 3A). In response to pro-ANP injection, but not saline, mean arterial pressure dropped significantly in corin-Tg but not WT mice (Figure 3B; P<0.05).
Corin Modulates HF in Mice With DCMc
To examine whether corin modulates HF, corin-Tg mice were backcrossed with DCMc mice on the same strain background. Female littermates were examined at 14 to 15 weeks. There was no significant difference in body weight or body:heart weight ratios (Figure S4). CREB Tg transcript levels did not change after backcrossing (P=0.41). Corin transcripts were higher in DCMc, corin-Tg mice than in DCMc mice (Figure 4A). Enhanced expression of corin protein was also found (Figure 4B–4D). Higher blood levels of soluble corin were detected in DCMc, corin-Tg mice than DCMc mice (P<0.05; n=4–5 each group). Transcripts for ANP (1.7-fold; P<0.05; Figure S5) and BNP (1.4-fold; P<0.001; Figure S6) were higher in DCMc, corin-Tg than in DCMc mice. Consistent with this observation, levels of cGMP were significantly higher in DCMc, corin-Tg mice (Figure S7; P<0.05). DCMc, corin-Tg mice had reduced interstitial and perivascular cardiac fibrosis (54% lower; P<0.05; n=4–5 each group; Figure 4E and 4F) by Masson trichrome staining. Transcripts for collagen I (P<0.01) and collagen III (P<0.05) were lower in DCMc, corin-Tg mice (Figures S8 and S9). There was a trend to lower transforming growth factor-β levels, but chymase 1, matrix metalloproteinases 9, and furin transcripts were not different between the 2 groups (Figures S10–S13). DCMc, corin-Tg mice had better contractile function with a higher ejection fraction % (P<0.01; Figure 4G) and fractional shortening (23.0±2.4% versus 12.9±1.3%; P<0.01) than DCMc mice despite similar left ventricle internal dimensions (Figure S14). HF was significantly reduced in DCMc, corin Tg versus DCMc mice as assessed by reduced alveolar edema and congestion (Figure 4H and 4I; P<0.001) and reduced lung water (lung wet:dry ratio, P<0.05). Most importantly, the survival of DCMc, corin-Tg mice was significantly longer than the survival of DCMc mice (Figure 4J; P<0.0001).
In patients with DCM, progressive HF is a major cause of morbidity and mortality with high social costs. As such, there is a critical need to discover mechanisms that regulate HF development and progression to create new diagnostic, treatment, and prevention strategies. Corin’s cardiac-selective expression and its key role in regulating the NP system make it a potential biomarker of acute HF in the setting of diminished systolic function.3–5 Cardiac transcripts25 and circulating levels of corin3–5,24 are reduced in patients with HF and DCM but not in all cardiac conditions, particularly those involving hypertrophy.7,26,28 Still, the functional role of corin in DCM has not been established. In a well-characterized model of HF and DCM,19–23 we confirmed that myocardial corin transcripts (and protein levels) were reduced. Similar reductions in corin expression were observed in a model of HF induced by arterial venous shunting.27 Restoration of corin levels in DCMc mice markedly reduced development of cardiomyopathy and HF. There were significant reductions in myocardial fibrosis and improvements in contractile indices (fractional shortening, ejection fraction) in DCMc, corin-Tg versus DCMc mice. HF was also improved in DCMc, corin-Tg mice as assessed by objective indices of lung water and congestion. Perhaps the most compelling finding was that restoration of corin levels significantly increased the survival of DCMc, corin –Tg mice versus DCMc mice.
There are several potential mechanisms through which corin and the NP system may modulate the development of HF. Corin cleaves pro-ANP to ANP, which has enhanced physiologic effects.9,30 ANP increases salt and water excretion which should reduce the salt and water retention of HF.16,31 We found low levels of circulating corin and impaired pro-ANP cleavage in patients with acute decompensated HF suggesting that low corin levels might contribute to this syndrome of salt and water retention in some patients.3,4 Indeed, corin deficiency reduces sodium excretion in response to high-salt diets.32 Our data show that overexpression of corin increases physiologic responses to pro-ANP, increases cGMP levels, and reduces fluid retention in mice with DCMc. Although the relative contributions of cardiac and circulating corin to NP cleavage are still unknown, patients with HF respond to ANP infusions with increased cGMP levels and improved long-term prognosis.33,34 ANP also enhances vasodilation, which can increase cardiac output in the presence of reduced cardiac function.
There is increasing evidence that corin also may cleave pro-BNP to BNP.10,11,13,14 Recent studies have linked a hypofunctional polymorphism in corin to diminished pro-BNP cleavage and worse outcomes.35 Some patients with chronic HF appear to have abnormal processing of pro-BNP to BNP fragments with diminished biologic activity.36 Still, the therapeutic value of BNP (Natrecor/Nesiritide) therapy in HF patients is controversial, and a large-scale clinical trial showed no significant improvement in symptoms or mortality.37
In addition to natriuretic and vasodilatory effects, ANP and BNP also affect apoptosis, inflammation, and cardiac fibrosis—each of these mechanisms may affect the progression of cardiomyopathies.38,39 Indeed, deletion of the receptor for ANP and BNP (natriuretic peptide receptor A) accelerated mortality in mice with DCM.40 Cardiac fibrosis is significant in all DCMc mice by 8 weeks of age though no significant apoptosis or inflammation was appreciated.19 Cardiac fibrosis was also seen in knockout mice lacking ANP, BNP.41,42 Cardiac fibrosis affects diastolic and systolic dysfunction and contributes to the development of HF.43 When analyzed at 14 to 15 weeks of age, hearts from DCMc, corin-Tg mice showed significantly less interstitial and perivascular ventricular fibrosis than DCM mice. In addition, the DCMc, corin-Tg mice had increased corin levels, cGMP levels, and ANP and BNP transcripts. ANP and BNP inhibit collagen synthesis and proliferation of cardiac fibroblasts; which in turn inhibits cardiac fibrosis in vivo.39,42 Thus, the reduced fibrosis seen in DCMc, corin-Tg mice may be attributable to increased activity of the NP system and may contribute to the improved ventricular function seen in these mice.
In summary, consistent with findings in humans with HF and DCM,25 we find that corin expression is significantly reduced in experimental DCMc and HF. In a recently published study, corin-deficient KitW-sh/W-sh mice developed rapidly progressive cardiac dilation and loss of cardiac function after aortic banding.44 These findings, in addition to the cardiac-selective expression of corin and its role as regulator of the NP system, make corin an attractive biomarker for DCM and HF. Beyond its potential diagnostic value, corin appears to play a key functional role in DCM and HF where enhanced expression is associated with reduced myocardial fibrosis, enhanced contractility, prevention of HF, and prolongation of life. Further studies of corin in other types of HF and cardiomyopathies, for instance, hypertensive heart disease and chronic myocardial infarction, will be necessary to determine the value of corin as a biomarker and potential therapeutic agent.
Corin is a key regulator of the NP system, which modulates salt and water balance in HF. However, levels of corin are unexpectedly reduced in humans and mice with DCM. Increasing cardiac corin expression in mice with DCM enhances ANP and BNP expression, improves cardiac function, reduces cardiac fibrosis, and prolongs survival. Thus in addition to its value as a potential biomarker, strategies for increasing corin levels in DCM may mitigate the progression of cardiac fibrosis, HF, systolic dysfunction, and death.
We gratefully acknowledge the initial contributions of Brian Robinson, Roxanne Wadia, and Natalia Zhidkova.
Sources of Funding
This work was supported by
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Novelty and Significance
What Is New?
In a model of heart failure we found:
Reduced heart function and measurable heart failure
High levels of natriuretic peptides atrial natriuretic peptide and brain natriuretic peptide
Reduced levels of corin, a novel heart protein
Increasing corin in the heart of normal mice:
Reduced blood pressure in response to pro-atrial natriuretic peptide
Increased cGMP which regulates blood pressure
Increasing the level of corin in mice with enlarged hearts:
Reduced heart scarring
Prevented heart failure
Increased heart function
What Is Relevant?
Hypertension often causes heart failure
Corin activates natriuretic peptides to reduce blood pressure
Coring polymorphisms may cause heart problems in patients with hypertension
Increasing corin levels in heart failure prevents loss of heart function, fluid retention, heart scarring, and early death
Corin is an attractive biomarker for heart failure and cardiomyopathy. These results also provide the first experimental evidence that corin expression may reduce heart scarring, improve heart function, prevent heart failure, and increase survival.