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Corin: new insights into the natriuretic peptide system

2008; Elsevier BV; Volume: 75; Issue: 2 Linguagem: Inglês

10.1038/ki.2008.418

1523-1755

Qingyu Wu, Ye Olivia Xu-Cai, Shenghan Chen, Wei Wang,

Hormonal Regulation and Hypertension

Natriuretic peptides are important in regulating salt and body-fluid balance. In cells, these peptides are made as precursor forms that are converted to active forms by proteolyic processing. Corin is a transmembrane serine protease identified in the heart. Corin converts pro-atrial natriuretic peptide (pro-ANP) to active ANP in a sequence-specific manner. In mice, lack of corin prevents the conversion of pro-ANP to ANP and causes salt-sensitive hypertension. The hypertensive phenotype is exacerbated when the mice become pregnant. In humans, single nucleotide polymorphisms in the corin gene have been identified in African Americans with hypertension and cardiac hypertrophy. These data indicate that corin is important in maintaining normal blood pressure in vivo and that corin deficiency may contribute to hypertension and heart disease in patients. Natriuretic peptides are important in regulating salt and body-fluid balance. In cells, these peptides are made as precursor forms that are converted to active forms by proteolyic processing. Corin is a transmembrane serine protease identified in the heart. Corin converts pro-atrial natriuretic peptide (pro-ANP) to active ANP in a sequence-specific manner. In mice, lack of corin prevents the conversion of pro-ANP to ANP and causes salt-sensitive hypertension. The hypertensive phenotype is exacerbated when the mice become pregnant. In humans, single nucleotide polymorphisms in the corin gene have been identified in African Americans with hypertension and cardiac hypertrophy. These data indicate that corin is important in maintaining normal blood pressure in vivo and that corin deficiency may contribute to hypertension and heart disease in patients. The natriuretic peptide system, which was first discovered in the early 1980s by Adolfo de Bold,1.de Bold A.J. Borenstein H.B. Veress A.T. et al.A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats.Life Sci. 1981; 28: 89-94Google Scholar is an endocrine mechanism that regulates salt and body fluid balance. The system is conserved in all vertebrates ranging from the most primitive species such as hagfish to humans. For many teleost species, natriuretic peptides are critical for their adaptation to low- and high-salt environments. Salmon and some eels, for example, live in both fresh and salty water during different phases of their life cycles. Natriuretic peptides have been identified in these animals.2.Tervonen V. Arjamaa O. Kokkonen K. et al.A novel cardiac hormone related to A-, B- and C-type natriuretic peptides.Endocrinology. 1998; 139: 4021-4025Google Scholar, 3.Tsukada T. Takei Y. Integrative approach to osmoregulatory action of atrial natriuretic peptide in seawater eels.Gen Comp Endocrinol. 2006; 147: 31-38Google Scholar In Japanese eel (Anguilla japonica), natriuretic peptides are shown to be important in controlling water drinking and regulating salt absorption and excretion in gills, guts, and kidneys when the animals switch between low-salt freshwater and high-salt seawater.3.Tsukada T. Takei Y. Integrative approach to osmoregulatory action of atrial natriuretic peptide in seawater eels.Gen Comp Endocrinol. 2006; 147: 31-38Google Scholar Unlike the teleost fish, terrestrial mammals do not have to deal with constant surroundings of dangerously low or high salt. Nevertheless, natriuretic peptides are important in maintaining blood volume and electrolyte balance, as drinking water and food contents on earth may vary dramatically in different seasons and locations. The mammalian natriuretic peptide family has three structurally related members, namely atrial natriuretic peptide (ANP) or atrial natriuretic factor, brain or B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). ANP and BNP are made primarily in the heart whereas CNP is made in many organs including the brain, kidney, bone, and vessels. The primary function of ANP and BNP is to regulate blood volume and pressure. Under high blood volume or pressure, ANP and BNP are released into the circulation. In target organs such as kidneys and peripheral blood vessels, the peptides activate their receptor, natriuretic peptide receptor-A (NPR-A), and increase intracellular cGMP production, leading to natriuresis, diuresis, and vasodilation, and thereby lowering blood volume and pressure. ANP and BNP also suppress renin and endothelin release, which is an additional mechanism to regulate vascular tone. In contrast, CNP binds to natriuretic peptide receptor-B (NPR-B), inhibits vascular smooth muscle cell proliferation, and prevents coronary artery restenosis in animal models. CNP and NPR-B also have a major role in chondrocyte differentiation and bone formation.4.Chusho H. Tamura N. Ogawa Y. et al.Dwarfism and early death in mice lacking C-type natriuretic peptide.Proc Natl Acad Sci USA. 2001; 98: 4016-4021Google Scholar There is a third natriuretic peptide receptor, NPR-C, which binds all three peptides and remove them from the circulation. Several recent articles have reviewed various aspects of the natriuretic peptide system in depth.5.Lee C.Y. Burnett Jr, J.C. Natriuretic peptides and therapeutic applications.Heart Fail Rev. 2007; 12: 131-142Google Scholar, 6.McGrath M.F. de Bold M.L. de Bold A.J. The endocrine function of the heart.Trends Endocrinol Metab. 2005; 16: 469-477Google Scholar, 7.Potter L.R. Abbey-Hosch S. Dickey D.M. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions.Endocr Rev. 2006; 27: 47-72Google Scholar Like many peptide hormones, natriuretic peptides are synthesized as prepropeptides. After the signal peptide is removed, an additional proteolytic cleavage is required to convert the inactive propeptide to an active peptide (Figure 1 ). This post-translational processing step represents an important mechanism in regulating the activity of the natriuretic peptides, but identifying the endogenous processing enzymes was challenging. Several laboratories, for example, showed that thrombin and kellikreins could process pro-ANP in vitro.8.Seidah N.G. Cromlish J.A. Hamelin J. et al.Homologous IRCM-serine protease 1 from pituitary, heart atrium and ventricle: a common pro-hormone maturation enzyme?.Biosci Rep. 1986; 6: 835-844Google Scholar However, it was difficult to prove that the observed activities were specific and to show that these enzymes function as the physiological pro-ANP convertase in vivo. Other studies also indicated that a cell membrane-associated high-molecular weight trypsin-like enzyme in the heart may be the pro-ANP convertase, but purification of this enzyme was unsuccessful.9.Imada T. Takayanagi R. Inagami T. Atrioactivase, a specific peptidase in bovine atria for the processing of pro-atrial natriuretic factor. Purification and characterization.J Biol Chem. 1988; 263: 9515-9519Google Scholar As a result, the enzymes responsible for processing natriuretic peptides remain undefined for many years. The discovery of corin was serendipitous. Our interests in serine proteases started with thrombin, a blood-clotting enzyme whose activity is greatly enhanced in the presence of cell membranes. Later, we extended our work to include transmembrane serine proteases such as enteropeptidase and hepsin,10.Wu Q. Type II transmembrane serine proteases.Curr Top Dev Biol. 2003; 54: 167-206Google Scholar which subsequently led us to search for other transmembrane serine proteases in the cardiovascular system. By searching databases for genes with trypsin-like sequences, we cloned a new membrane serine protease from the human heart and named it corin for its cardiac expression.11.Yan W. Sheng N. Seto M. et al.Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart.J Biol Chem. 1999; 274: 14926-14935Google Scholar As shown in Figure 2 , corin is a mosaic protein consisting of a transmembrane domain near the N terminus and two frizzled-like domains, eight LDL receptor repeats, a scavenger receptor –like domain, and a trypsin-like protease domain at the C terminus. Such a protein domain arrangement is unique. To date, corin remains the only known trypsin-like protease that contains frizzled-like domains, which are mostly associated with Wnt signaling proteins. Moreover, human corin, as a serine protease, is exceptionally large with 1042 amino acids. There are 19 predicted N-linked glycosylation sites in its extracellular region.11.Yan W. Sheng N. Seto M. et al.Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart.J Biol Chem. 1999; 274: 14926-14935Google Scholar On SDS–polyacrylamide gel electrophoresis and western analysis, native and recombinant human, rat, and mouse corin proteins had apparent molecular masses of ∼150–200 kDa.12.Gladysheva I.P. Robinson B.R. Houng A.K. et al.Corin is co-expressed with pro-ANP and localized on the cardiomyocyte surface in both zymogen and catalytically active forms.J Mol Cell Cardiol. 2008; 44: 131-142Google Scholar, 13.Hooper J.D. Scarman A.L. Clarke B.E. et al.Localization of the mosaic transmembrane serine protease corin to heart myocytes.Eur J Biochem. 2000; 267: 6931-6937Google Scholar, 14.Liao X. Wang W. Chen S. et al.Role of glycosylation in corin zymogen activation.J Biol Chem. 2007; 282: 27728-27735Google Scholar, 15.Yan W. Wu F. Morser J. et al.Corin, a transmembrane cardiac serine protease, acts as a pro-atrial natriuretic peptide-converting enzyme.Proc Natl Acad Sci USA. 2000; 97: 8525-8529Google Scholar The human corin gene is on chromosome 4p12–13 with 22 exons and spans >200 kb,16.Pan J. Hinzmann B. Yan W. et al.Genomic structures of the human and murine corin genes and functional GATA elements in their promoters.J Biol Chem. 2002; 277: 38390-38398Google Scholar making it one of the biggest protease genes known to date. Corin is made primarily in the heart. We and others detected corin mRNA and protein in fetal and adult cardiomyocytes.11.Yan W. Sheng N. Seto M. et al.Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart.J Biol Chem. 1999; 274: 14926-14935Google Scholar, 13.Hooper J.D. Scarman A.L. Clarke B.E. et al.Localization of the mosaic transmembrane serine protease corin to heart myocytes.Eur J Biochem. 2000; 267: 6931-6937Google Scholar Corin mRNA expression appeared to be higher in the atrium than the ventricle (Figure 2). Corin mRNA was also found in scar myofibroblasts in rat hearts.17.Calderone A. Bel-Hadj S. Drapeau J. et al.Scar myofibroblasts of the infarcted rat heart express natriuretic peptides.J Cell Physiol. 2006; 207: 165-173Google Scholar Lower levels of corin mRNA were detected in other tissues, including developing kidneys and bones.11.Yan W. Sheng N. Seto M. et al.Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart.J Biol Chem. 1999; 274: 14926-14935Google Scholar Most recently, corin mRNA and protein were detected in mouse skin hair follicles.18.Enshell-Seijffers D. Lindon C. Morgan B.A. The serine protease corin is a novel modifier of the agouti pathway.Development. 2008; 135: 217-225Google Scholar In contrast, corin mRNA was not found in other muscle-rich tissues, such as stomach, small intestine, bladder, skeletal muscle, and nonpregnant uterus.11.Yan W. Sheng N. Seto M. et al.Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart.J Biol Chem. 1999; 274: 14926-14935Google Scholar We next set out to identify corin function. Because corin is a cardiac transmembrane protease with trypsin-like substrate specificity, it is likely that the corin substrate is a protein in the heart that is cleaved at a basic amino acid. Pro-ANP, which is made in the heart and proteolytically activated at Arg-98, could be a candidate substrate for corin. We did biochemical and cellular studies to test this hypothesis. In cell- and purified protein-based assays, corin converted pro-ANP to ANP in a sequence-specific manner.15.Yan W. Wu F. Morser J. et al.Corin, a transmembrane cardiac serine protease, acts as a pro-atrial natriuretic peptide-converting enzyme.Proc Natl Acad Sci USA. 2000; 97: 8525-8529Google Scholar, 19.Knappe S. Wu F. Madlansacay M.R. et al.Identification of domain structures in the propeptide of corin essential for the processing of proatrial natriuretic peptide.J Biol Chem. 2004; 279: 34464-34471Google Scholar, 20.Knappe S. Wu F. Masikat M.R. et al.Functional analysis of the transmembrane domain and activation cleavage of human corin.J Biol Chem. 2003; 278: 52363-52370Google Scholar In cultured cardiomyocytes, overexpression of a negative mutant corin or transfection of small interfering RNA against the corin gene blocked pro-ANP processing,21.Wu F. Yan W. Pan J. et al.Processing of pro-atrial natriuretic peptide by corin in cardiac myocytes.J Biol Chem. 2002; 277: 16900-16905Google Scholar suggesting that corin is the pro-ANP convertase. To define the functional importance of corin in vivo, we made corin-null mice and showed that atrial tissues from these mice had pro-ANP but no ANP, indicating that pro-ANP processing was abolished in the knockout mice.22.Chan J.C. Knudson O. Wu F. et al.Hypertension in mice lacking the proatrial natriuretic peptide convertase corin.Proc Natl Acad Sci USA. 2005; 102: 785-790Google Scholar Infusion of a soluble corin into these mice transiently restored pro-ANP processing, resulting in the release of active ANP into the circulation. These results have established corin as the physiological pro-ANP convertase and solved a long-standing puzzle in natriuretic peptide biology.23.Davenport R.J. Worth its salt. Elusive enzyme generates hormone that lowers blood pressure.Sci Aging Knowledge Environ. 2005; 2005: nf5Google Scholar, 24.Potter L.R. 'Corination' of the proANP converting enzyme.Cell Metab. 2005; 1: 88-90Google Scholar In cell-based assays, corin also cleaved pro-BNP, although the reaction was less efficient than that for pro-ANP.15.Yan W. Wu F. Morser J. et al.Corin, a transmembrane cardiac serine protease, acts as a pro-atrial natriuretic peptide-converting enzyme.Proc Natl Acad Sci USA. 2000; 97: 8525-8529Google Scholar Previous reports suggested that other enzymes may also process pro-BNP.25.Sawada Y. Suda M. Yokoyama H. et al.Stretch-induced hypertrophic growth of cardiocytes and processing of brain-type natriuretic peptide are controlled by proprotein-processing endoprotease furin.J Biol Chem. 1997; 272: 20545-20554Google Scholar Further studies are needed to define the pro-BNP convertase in vivo. In contrast, corin did not cleave pro-CNP in similar experiments.26.Wu C. Wu F. Pan J. et al.Furin-mediated processing of Pro-C-type natriuretic peptide.J Biol Chem. 2003; 278: 25847-25852Google Scholar In human kidney cells and chondrocytes, recombinant human pro-CNP was processed without corin. Corin overexpression did not enhance pro-CNP processing in these cells. The results are consistent with the fact that the pro-CNP cleavage sequence differs from that in pro-ANP and pro-BNP, and the fact that pro-CNP is processed intracellularly, whereas corin acts extracellularly. We went on and tested furin, a trans-Golgi enzyme, as a candidate for pro-CNP convertase. Using furin-deficient LoVo cells and purified recombinant furin protein, we showed that pro-CNP is activated by furin.26.Wu C. Wu F. Pan J. et al.Furin-mediated processing of Pro-C-type natriuretic peptide.J Biol Chem. 2003; 278: 25847-25852Google Scholar Thus, natriuretic peptides are processed by different enzymes, although they share significant sequence and structural similarities. The ANP pathway is important in regulating blood pressure. Knockout mice lacking ANP or NPR-A are hypertensive.27.John S.W. Krege J.H. Oliver P.M. et al.Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension.Science. 1995; 267: 679-681Google Scholar, 28.Lopez M.J. Wong S.K. Kishimoto I. et al.Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide.Nature. 1995; 378: 65-68Google Scholar If corin is essential for pro-ANP activation, mice with corin deficiency are expected to have a similar hypertensive phenotype. Using radiotelemetry, we found that corin-null mice, which are viable and fertile, indeed were hypertensive.22.Chan J.C. Knudson O. Wu F. et al.Hypertension in mice lacking the proatrial natriuretic peptide convertase corin.Proc Natl Acad Sci USA. 2005; 102: 785-790Google Scholar Both male and female corin-null mice had elevated systolic, diastolic, and mean arterial blood pressure compared to that in wild-type controls. Blood pressure increased further when the mice were fed a high-salt diet. Such a phenotype was also reported in ANP-null mice.27.John S.W. Krege J.H. Oliver P.M. et al.Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension.Science. 1995; 267: 679-681Google Scholar The data are consistent with corin being the pro-ANP convertase and show the importance of corin in maintaining normal blood pressure in vivo. In Northern blotting, corin mRNA was found only in the heart. By in situ hybridization, however, abundant corin mRNA was detected in the decidual cells of the pregnant mouse uterus.11.Yan W. Sheng N. Seto M. et al.Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart.J Biol Chem. 1999; 274: 14926-14935Google Scholar Corin mRNA was also found in human endometrium and leiomyosarcoma cells.11.Yan W. Sheng N. Seto M. et al.Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart.J Biol Chem. 1999; 274: 14926-14935Google Scholar The finding of uterine corin expression was unexpected but may suggest a role of corin in pregnancy. As blood volume expands significantly during pregnancy, maintaining normal blood pressure becomes increasingly challenging. As a result, additional regulations may be needed to deal with this special condition. It is possible that the uterine corin expression is a previously unrecognized mechanism to prevent hypertension during pregnancy. If this hypothesis is correct, we should expect further blood pressure increase when corin-null mice become pregnant. By telemetric monitoring, we indeed found a significant increase of systolic blood pressure in pregnant corin-null mice, which reached the highest level at mid-gestation but eventually returned to pre-pregnancy levels after delivery.22.Chan J.C. Knudson O. Wu F. et al.Hypertension in mice lacking the proatrial natriuretic peptide convertase corin.Proc Natl Acad Sci USA. 2005; 102: 785-790Google Scholar The pregnant corin-null mice also develop late-gestational proteinuria, reminiscent of preeclampsia in patients. Histological analysis indicated endotheliosis and ischemic changes in glomeruli in these mice. These results suggest that corin may be exploited during pregnancy to regulate hemodynamic changes and prevent hypertension. Corin-null mice may be used as a new model of preeclampsia. Single nucleotide polymorphisms (SNPs) in the ANP gene promoter or a deletion in the NPR-A gene promoter are associated with patients with hypertension and cardiac hypertrophy, suggesting that defects in the ANP pathway may contribute to hypertensive disease.29.Nakayama T. Soma M. Takahashi Y. et al.Functional deletion mutation of the 5′-flanking region of type A human natriuretic peptide receptor gene and its association with essential hypertension and left ventricular hypertrophy in the Japanese.Circ Res. 2000; 86: 841-845Google Scholar, 30.Rubattu S. Bigatti G. Evangelista A. et al.Association of atrial natriuretic peptide and type a natriuretic peptide receptor gene polymorphisms with left ventricular mass in human essential hypertension.J Am Coll Cardiol. 2006; 48: 499-505Google Scholar Recently, two nonsynonymous and nonconservative SNPs (T555I and Q568P) are found in the human corin gene.31.Dries D.L. Victor R.G. Rame J.E. et al.Corin gene minor allele defined by 2 missense mutations is common in blacks and associated with high blood pressure and hypertension.Circulation. 2005; 112: 2403-2410Google Scholar These two SNPs are in complete linkage disequilibrium in the population and, as a result, are colocalized in a minor allele (I555/P568). Epidemiological studies of large population-based cohorts, including the Dallas Heart Study, the Multi-Ethnic Study of Atherosclerosis (MESA), and the Chicago Genetics of Hypertension Study, have shown that the minor corin I555/P568 allele is more common in African Americans than in Caucasians (∼12 vs <0.2% carrying one or more copies of the allele) and associated with an increased risk for hypertension.31.Dries D.L. Victor R.G. Rame J.E. et al.Corin gene minor allele defined by 2 missense mutations is common in blacks and associated with high blood pressure and hypertension.Circulation. 2005; 112: 2403-2410Google Scholar In addition, the I555/P568 corin minor allele was reported to be associated with an enhanced concentric cardiac hypertrophy in response to high systolic blood pressure in African Americans from the Dallas Heart and MESA cohorts.32.Rame J.E. Drazner M.H. Post W. et al.Corin I555(P568) allele is associated with enhanced cardiac hypertrophic response to increased systemic afterload.Hypertension. 2007; 49: 857-864Google Scholar Patients with this corin allele had a greater left ventricular mass compared to that of control patients with a wild-type allele but similar systolic blood pressure. The data linking the corin gene variant to myocardial pathology in patients is intriguing.33.Burnett Jr, J.C. Olson T.M. Natriuretic peptides and myocardial structure: insights from population genetics.Hypertension. 2007; 49: 765-766Google Scholar Earlier animal studies have indicated that the ANP pathway has a local anti-hypertrophy function in the heart, which is independent of its systemic action on blood pressure.34.Molkentin J.D. A friend within the heart: natriuretic peptide receptor signaling.J Clin Invest. 2003; 111: 1275-1277Google Scholar Consistently, we also showed that corin-null mice developed cardiac hypertrophy.22.Chan J.C. Knudson O. Wu F. et al.Hypertension in mice lacking the proatrial natriuretic peptide convertase corin.Proc Natl Acad Sci USA. 2005; 102: 785-790Google Scholar These data suggest that corin deficiency may contribute to hypertension and heart failure in African Americans, a population known for its high prevalence of these cardiovascular diseases. For more than a quarter century, significant knowledge has been gained for the natriuretic peptides and their biological function and therapeutic potential.35.Burnett Jr, J.C. Novel therapeutic directions for the natriuretic peptides in cardiovascular diseases: what's on the horizon.J Cardiol. 2006; 48: 235-241Google Scholar And yet, much more remains to be learned. For example, both ANP and BNP are thought to bind NPR-A, but this concept may not be satisfactory. The affinity of ANP binding to the receptor was shown to be ∼10 times higher than that for BNP binding.36.Koller K.J. Goeddel D.V. Molecular biology of the natriuretic peptides and their receptors.Circulation. 1992; 86: 1081-1088Google Scholar How, then, could BNP bind to the receptor in the presence of similar levels of ANP? More importantly, ANP- and BNP-knockout mice have very different phenotypes.27.John S.W. Krege J.H. Oliver P.M. et al.Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension.Science. 1995; 267: 679-681Google Scholar, 37.Tamura N. Ogawa Y. Chusho H. et al.Cardiac fibrosis in mice lacking brain natriuretic peptide.Proc Natl Acad Sci USA. 2000; 97: 4239-4244Google Scholar If these peptides can substitute each other for the same receptor, why do ANP- and BNP-knockout mice have a phenotype at all? Some studies suggest that there may be another receptor for BNP but its identity remains unknown.38.Goy M.F. Oliver P.M. Purdy K.E. et al.Evidence for a novel natriuretic peptide receptor that prefers brain natriuretic peptide over atrial natriuretic peptide.Biochem J. 2001; 358: 379-387Google Scholar As ANP and BNP are being developed to treat patients with heart failure,5.Lee C.Y. Burnett Jr, J.C. Natriuretic peptides and therapeutic applications.Heart Fail Rev. 2007; 12: 131-142Google Scholar answers to these questions will be critical to understand the therapeutic efficacy and unwanted side effects of these peptides. The discovery of corin and characterization of the hypertensive phenotype in corin-null mice highlight the importance of natriuretic peptide processing and point to a long-neglected area in this field. For years, radioimmunoassay and enzyme-linked immunosorbent assay are used to measure ANP and BNP in a variety of clinical and experimental settings. The antibodies used in these assays may not distinguish processed from unprocessed natriuretic peptides. For example, antibodies bind to ANP may also recognize pro-ANP. As a result, it is not clear which molecular forms, that is, ANP, pro-ANP, or both, are measured in these assays. Similar situation applies to BNP and pro-BNP assays. As plasma BNP is used as a diagnostic test for heart failure,39.Ruskoaho H. Cardiac hormones as diagnostic tools in heart failure.Endocr Rev. 2003; 24: 341-356Google Scholar this issue is of clinical importance. Corin is a newly discovered enzyme. We are only at the beginning toward understanding its biology.40.Wu Q. The serine protease corin in cardiovascular biology and disease.Front Biosci. 2007; 12: 4179-4190Google Scholar Many questions remain regarding corin function and regulation under physiological and pathological conditions. In animal models of heart failure, for example, corin mRNA expression was shown to be upregulated in the ventricle41.Jiang W. Cai D.Y. Pan C.S. et al.Changes in production and metabolism of brain natriuretic peptide in rats with myocardial necrosis.Eur J Pharmacol. 2005; 507: 153-162Google Scholar, 42.Tran K.L. Lu X. Lei M. et al.Upregulation of corin gene expression in hypertrophic cardiomyocytes and failing myocardium.Am J Physiol Heart Circ Physiol. 2004; 287: H1625-H1631Google Scholar but downregulated in the atrium.43.Langenickel T.H. Pagel I. Buttgereit J. et al.Rat corin gene: molecular cloning and reduced expression in experimental heart failure.Am J Physiol Heart Circ Physiol. 2004; 287: H1516-H1521Google Scholar It appears that corin regulation is a part of the pathological process during heart failure but the results need to be verified in samples from patients with heart failure. Further studies of corin should provide new insights into the natriuretic peptide system and may help to design new strategies to diagnose and treat hypertension and heart disease. The authors declare no competing interests. We thank many former and current laboratory members who contributed corin studies, especially Dr Wei Yan who prepared the picture in Figure 2. We also thank Ms Robin Lewis for helping with illustrations and Dr Edward Plow and Dr Martin Schreiber for their support. This work was supported by grants from the Bakken Heart-Brain Institute, the Cleveland Clinic, the National Institutes of Health (HL089298 to Q.W.), and the Ralph Wilson Medical Research Foundation.