Relevance of Molecular Forms of Brain Natriuretic Peptide for Natriuretic Peptide Research
2007; Lippincott Williams & Wilkins; Volume: 49; Issue: 5 Linguagem: Inglês
10.1161/hypertensionaha.107.087254
ISSN1524-4563
Autores Tópico(s)Receptor Mechanisms and Signaling
ResumoHomeHypertensionVol. 49, No. 5Relevance of Molecular Forms of Brain Natriuretic Peptide for Natriuretic Peptide Research Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBRelevance of Molecular Forms of Brain Natriuretic Peptide for Natriuretic Peptide Research Daniel L. Dries Daniel L. DriesDaniel L. Dries From the Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia. Originally published19 Mar 2007https://doi.org/10.1161/HYPERTENSIONAHA.107.087254Hypertension. 2007;49:971–973Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 19, 2007: Previous Version 1 The focus on brain natriuretic peptide (BNP) as a biomarker, the elevation of which is associated with adverse outcomes in persons with heart failure, has obscured recognition of the myriad beneficial and compensatory biological actions provided by this small peptide hormone. Both atrial and ventricular cardiomyocytes synthesize and release both atrial natriuretic peptide (ANP) and BNP in response to volume or pressure overload, most specifically, an increase in myocardial transmural distending pressure. These peptide hormones activate the natriuretic peptide receptor type A, which contains a guanylate–cyclase domain, and this leads to the production of cGMP and the activation of downstream signaling cascades. The resulting biological actions in target tissue include the following actions that are universally beneficial in the setting of hypertension, hypertensive heart disease, and heart failure: venous and arterial vasodilation, maintenance of appropriate intravascular volume by promoting natriuresis, opposing activation of the renin–angiotensin–aldosterone system, reduced secretion of endothelin, and attenuation of central and peripheral sympathetic activity.1 In addition, the natriuretic peptide system (NPS) functions as an autocrine/paracrine system that opposes the development of cardiac fibrosis and hypertrophy via pressure-independent mechanisms.2BNP is produced as prohormone that undergoes further processing (Figure). After removal of the 26 amino acid signal peptide from the prepro-BNP molecule, pro-BNP (1-108) is secreted from cardiomyocytes and interacts with an enzyme called corin, a transmembrane serine protease produced in cardiomyocytes, resulting in the production of a 76 amino acid amino terminal fragment (NT-BNP 1-76) and the biologically active 32 amino acid carboxyl fragment (BNP 77-108 or BNP-32).3 It is believed that the site of natriuretic peptide processing is the extracellular region of cardiomyocytes and possibly cardiac fibroblasts. Although corin appears to be unique in this capacity, other yet undiscovered enzymes may contribute to natriuretic peptide processing. Download figureDownload PowerPointBNP processing. BNP is produced as a prohormone that is processed into its biologically active, carboxyl-terminal fragment. The critical processing step occurs on the extracellular surface of cardiomyocytes when it interacts with corin, a type II transmembrane serine protease.The compensatory biological actions of the NPS become attenuated in the setting of systolic heart failure, and it appears that the degree of reduced compensatory actions parallels the severity of heart failure.4,5 The biological basis for the reduced compensatory actions of the NPS is multifactorial: homologous desensitization of the natriuretic peptide receptor type A; downregulation of natriuretic peptide receptor type A in target tissue; upregulation of phosphodiesterases, including phosphodiesterase 5, leading to enhanced cGMP degradation; and augmented neutral endopeptidase activity.1 An intriguing hypothesis states that impaired natriuretic peptide processing may contribute to the amelioration of the in vivo compensatory actions of the NPS in the setting of systolic heart failure. For example, a recent study6 that used Fourier transform ion cyclotron resonance mass spectrometry reported the absence of mature BNP-32 despite markedly elevated levels of BNP measured by the Biosite assay. However, incompletely characterized high-molecular forms of BNP were observed. These data raised speculation that the Biosite assay may not be measuring what we thought it was and fueled speculation that, in certain clinical settings, such as advanced heart failure, natriuretic peptide processing may be inefficient and incomplete.In this issue of Hypertension,7 Heublein et al demonstrate the cross-reactivity of various molecular forms of human BNP with commonly used commercial bioassays for BNP. The data demonstrate that the Biosite and Shionogi assays detect the biologically active forms of BNP (BNP 1-32 or 3-32) but do not measure NT-BNP (1-76) or unprocessed BNP (1-108). In contrast, the Roche NT-BNP assay measures NT-BNP (1-76), does not cross react with mature BNP1-32 or BNP3-32, but does demonstrate significant cross-reactivity with unprocessed BNP 1-108. The second significant finding reported by Heublein et al7 is the demonstration that unprocessed BNP (1-108) is biologically inactive, as illustrated by its inability to increase cGMP production in cardiomyocytes. Presumably, despite the fact that pro-BNP (1-108) possesses the disulfide ring required for biological activity of the natriuretic peptides, the tertiary structure of the larger BNP 1-108 molecule or resulting oligomerization prevents it from interacting effectively with the natriuretic peptide receptor type A receptor's ligand binding domain. The lack of biological activity of unprocessed BNP (1-108) has not been demonstrated previously. However, the importance of adequate natriuretic peptide processing to the adequate function of the NPS was inferred by the observation that the corin knockout mice develop hypertension in the setting of circulating unprocessed ANP.8 Interestingly, the administration of a recombinant form of soluble corin to the corin knockout mice resulted in rapid appearance of processed ANP in the plasma, a parallel increase in plasma cGMP, and an immediate decrease in systemic blood pressure.The data from Heublein et al7 provide the rationale and a methodologic framework to explore the epidemiology, molecular basis, and prognostic import of impaired natriuretic peptide processing in various disease states. Such endeavors may lead to novel therapeutic and preventive strategies across the spectrum of hypertensive heart disease. In particular, the data reported by Heublein et al7 demonstrate that 2 commonly used and validated bioassays (Biosite and Shiogoni) are specific for processed, biologically active BNP-32 and devoid of significant cross-reactivity with either NT-BNP (1-76) or pro-BNP (1-108). What is needed to address the research questions in this field is a specific assay for unprocessed pro-BNP (1-108). BioRad has reported the development of a specific bioassay for intact, unprocessed BNP 1-108 that should eventually be commercially available.9 The BioRad intact BNP assay uses a capture-antibody that reacts with epitopes in the "hinge region" (the region containing the cleavage site for corin) of the unprocessed BNP 1-108 molecule and a carboxyl-terminal detection antibody. The simultaneous measurement of BNP using the Biosite (or Shiogoni) and BioRad intact BNP assays allows the simultaneous measurement of processed, biologically active BNP (1-32 or 3-32) and unprocessed, biologically inactive BNP (1-108).There are intriguing questions that remain to be answered when considering the relationship of natriuretic peptide processing to the compensatory actions of the NPS in various disease states. One concept of potential relevance is that of "natriuretic peptide processing efficiency," which an investigator might define as the ratio of circulating biologically active BNP (1-32 or 3-32) to unprocessed, biologically inactive BNP (1-108) or the percentage of biologically active BNP within the "total natriuretic peptide demand" BNP pool, defined as the sum total of biologically active BNP and unprocessed pro-BNP. Perhaps these concepts, when considered in the context of the well-elucidated biology of the NPS, might provide additional prognostic information in patients with heart failure and possibly identify patients who might benefit most from exogenous natriuretic peptide therapy. Although elevated levels of BNP are consistently associated with adverse outcomes in heart failure populations of mixed severity, a recent report within a relatively small but homogenous population of patients with advanced heart failure demonstrated that nonsurvivors compared with survivors had lower BNP levels (Biosite).10 Could it be that a subpopulation of persons with advanced heart failure and a low Biosite BNP level might actually be in a "BNP deficient" state? A BNP deficient state might not be appreciated by measuring only biologically active BNP but rather by comparing the amount of biologically active BNP as a percentage of the "total natriuretic peptide demand."The demonstration of unprocessed BNP (1-108) in advanced human heart failure9 leads to speculation that there may be a deficiency in natriuretic peptide processing in this setting, and this may contribute to disease progression by ameliorating the compensatory actions of the NPS. Corin appears to be unique in its capacity as the "pro-ANP/BNP convertase"; therefore, the natriuretic processing capacity of corin may be overwhelmed when the transcription of ANP and BNP is excessive. Is the corin gene upregulated in heart failure to help maintain natriuretic peptide processing efficiency? A priori considerations would lead one to predict a parallel increase in corin, ANP, and BNP transcription based an inspection of their promoter regions; the human corin, ANP, and BNP genes contain similar transcriptional factor binding sites, including functional GATA-4 binding domains.11 However, the 2 studies of corin expression in animal models of heart failure report conflicting results, with1 reporting an increase12 and the other a decrease13 in corin expression. In a related human study that examined the correlation of corin and BNP gene expression in human hearts obtained at the time of heart transplant, an unexpected inverse relationship was observed14; corin gene expression declined as BNP gene expression increased, perhaps providing the molecular background for impaired natriuretic peptide processing. Recently, a minor allele in the human corin gene, defined by 2 nonconservative, nonsynonymous polymorphisms in complete linkage disequilibrium, was demonstrated to be common in persons of African descent, associated with higher blood pressure, an increased risk for hypertension, and an enhanced cardiac hypertrophic response to pressure overload.15,16 The yet-unproven hypothesis underlying the association of the corin I555 (P568) allele with these phenotypes is that natriuretic peptide processing is impaired in the presence of the minor corin allele.A better understanding of the physiology of natriuretic peptide processing will be an important area for future research with the field of natriuretic peptide physiology. The present data from Heublein et al,7 demonstrating the immunoreactivity and bioactivity of various molecular forms of BNP, provide the rationale and a methodologic approach to continue these research efforts. The data have the potential to yield important insights that may also improve preventive and treatment strategies in hypertension, the cardiac response to hypertension, and established heart failure.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.DisclosuresNone.FootnotesCorrespondence to Daniel L. Dries, Penn Cardiovascular Institute, University of Pennsylvania, 6 Penn Tower, 3400 Spruce St, Philadelphia, PA 19104. E-mail [email protected] References 1 Potter LR, Abbey-Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev. 2006; 27: 47–72.CrossrefMedlineGoogle Scholar2 Holtwick R, van Eickels M, Skyrabin BV, Baba HA, Bubikat A, Begrow F, Schneider MD, Garbers DL, Kuhn M. Pressure independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase A′. J Clin Invest. 2003; 111: 1399–1407.CrossrefMedlineGoogle Scholar3 Yan W, Wu F, Morser J, Wu Q. Corin, a transmembrane cardiac serine protease, acts as a pro-atrial natriuretic peptide-converting enzyme. Proc Natl Acad Sci U S A. 2000; 97: 8525–8529.CrossrefMedlineGoogle Scholar4 Tsutamoto T, Kanamori T, Wada A, Kinoshita M. Uncoupling of atrial natriuretic peptide extraction and cyclic guanosine monophosphate production in the pulmonary circulation in patients with severe heart failure. J Am Coll Cardiol. 1992; 20: 541–546.CrossrefMedlineGoogle Scholar5 Tsutamoto T, Wada A, Maeda K, Hisanaga T, Maeda Y, Fukai D, Ohnishi M, Sugimoto Y, Kinoshita M. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation. 1997; 96: 509–516.CrossrefMedlineGoogle Scholar6 Hawkridge AM, Heublein DM, Bergen HR 3rd, Cataliotti A, Burnett JC Jr, Muddiman DC. Quantitative mass spectral evidence for the absence of circulating brain natriuretic peptide (BNP-32) in severe human heart failure. Proc Natl Acad Sci U S A. 2005; 102: 17442–17447.CrossrefMedlineGoogle Scholar7 Heublein DM, Huntley HK, Boerrigter G, Cataliotti A, Sandberg SM, Redfield MM, Burnett JC Jr. Immunoreactivity and guanosine 3′,5′-cyclic monophosphate activating actions of various molecular forms of human B-type natriuretic peptide. Hypertension. 2007; 49: 1114–1119.LinkGoogle Scholar8 Chan JC KO, Wu F, Morser J, Dole WP, Wu Q. Hypertension in mice lacking the proatrial natriuretic peptide convertase corin. Proc Natl Acad Sci U S A. 2005; 102: 785–790.CrossrefMedlineGoogle Scholar9 Giuliani I, Rieunier F, Larue C, Delagneau JF, Granier C, Pau B, Ferriere M, Saussine M, Cristol JP, Dupuy AM, Merigeon E, Merle D, Villard S. Assay for measurement of intact B-type natriuretic peptide prohormone in blood. Clin Chem. 2006; 52: 1054–1061.CrossrefMedlineGoogle Scholar10 Miller WL, Burnett JC Jr, Hartman KA, Henle MP, Burritt MF, Jaffe AS. Lower rather than higher levels of B-type natriuretic peptides (NT-pro-BNP and BNP) predict short-term mortality in end-stage heart failure patients treated with nesiritide. Am J Cardiol. 2005; 96: 837–841.CrossrefMedlineGoogle Scholar11 Pan J, Hinzmann B, Yan W, Wu F, Morser J, Wu Q. Genomic structures of the human and murine corin genes and functional GATA elements in their promoters. J Biol Chem. 2002; 277: 38390–38398.CrossrefMedlineGoogle Scholar12 Tran KL, Lu X, Lei M, Feng Q, Wu Q. Upregulation of corin gene expression in hypertrophic cardiomyocytes and failing myocardium. Am J Physiol Heart Circ Physiol. 2004; 287: H1625–H1631.CrossrefMedlineGoogle Scholar13 Langenickel TH, Pagel I, Buttgereit J, Tenner K, Lindner M, Dietz R, Willenbrock R, Bader M. Rat corin gene: molecular cloning and reduced expression in experimental heart failure. Am J Physiol Heart Circ Physiol. 2004; 287: H1516–H1521.CrossrefMedlineGoogle Scholar14 Dries DL, Cappola T. Corin gene expression inversely related to increased BNP expression in advanced cardiomyopathy: setting the stage for inefficient natriuretic peptide processing in heart failure. Circulation. 2005; 112: (Suppl II): 637.Google Scholar15 Dries DL, Victor RG, Rame JE, Cooper RS, Wu X, Zhu X, Leonard D, Ho SI, Wu Q, Post W, Drazner MH. Corin gene minor allele defined by 2 missense mutations is common in blacks and associated with high blood pressure and hypertension. Circulation. 2005; 112: 2403–2410.LinkGoogle Scholar16 Rame JE, Drazner MH, Post W, Peshock R, Lima J, Cooper RS, Dries DL. Corin I555(P568) allele is associated with enhanced cardiac hypertrophic response to increased systemic afterload. 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