Stretch-induced Hypertrophic Growth of Cardiocytes and Processing of Brain-type Natriuretic Peptide Are Controlled by Proprotein-processing Endoprotease Furin

Sawada, Yohei; Suda, Masashi; Yokoyama, Hironori; Kanda, Tsugiyasu; Sakamaki, Tatsuya; Tanaka, Shigeyasu; Nagai, Ryozo; Abe, Shuzo; Takeuchi, Toshiyuki

doi:10.1074/jbc.272.33.20545

Cited by 122 publications

(86 citation statements)

References 74 publications

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“…Moreover, this event occurs during or very close to exocytosis of the secretory granules, since the peptide stored in the heart consists almost solely of pro-sCP-sized material, while the secreted peptide is due to sCP-sized material. Finally, the furin motif Arg-X-X-Arg (Sawada et al 1997) is not present in pro-sCP (Tervonen et al 1998), precluding BNP-type processing. On the other hand, it is interesting to note that the gene, cDNA and amino acid sequence of sCP (Tervonen et al 1998, Majalahti-Palviainen et al 2000 show a mixture of features typical of all three previously known mammalian natriuretic peptide subgroups, ANP, BNP and CNP.…”

Section: Discussionmentioning

confidence: 99%

Novel cardiac peptide hormone in several teleosts

Tervonen

Ruskoaho²,

Vuolteenaho³

2000

Journal of Endocrinology

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To find out the significance of the newest member of the natriuretic peptide family, salmon cardiac peptide (sCP), we have determined the distribution of the peptide and its mRNA as well as the tissue and plasma molecular forms in several teleosts. Using probes based on the salmon sCP cDNA in Northern blot analysis we found mRNA homologous to that of sCP to be present in the heart of 15 fish species representing nine different genera. We developed a specific RIA for the salmon 29 amino acid peptide to be able to study the distribution of the peptide in the heart and plasma of different fish species. Despite the probable interspecies differences in the peptide sequence, large quantities of immunoreactive sCP were found in the atrium, ventricle and plasma of most of the fish species studied, suggesting that a cardiac hormone homologous to sCP has an endocrine function in a large variety of teleost species. The molecular form of the hormone secreted and stored in the tissue was determined by gel filtration high pressure liquid chromatography. In salmon, as in most of the other fish species studied, the predominant immunoreactive sCP in plasma corresponded to the low molecular weight form, with a size similar to that of the biologically active 29 amino acid sCP (sCP-29), whereas the form stored in the heart corresponded to the high molecular weight pro-sCP-sized material. The form secreted by isolated perfused salmon ventricle, in the basal state as well as when mechanically loaded, was the sCP-29-sized peptide, thus ruling out the possibility that the conversion from high to low molecular weight material is caused by plasma proteases. In conclusion, sCP-like peptides are produced and secreted from the heart of a large number of different fish species. Their post-translational processing appears to be remarkably similar to that of mammalian atrial natriuretic peptide.

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Section: Discussionmentioning

confidence: 99%

Novel cardiac peptide hormone in several teleosts

Tervonen

Ruskoaho²,

Vuolteenaho³

2000

Journal of Endocrinology

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“…NT-proBNPspecific MAbs (with the recognized region as s subscript) 5B6 [1][2][3][4][5][6][7][8][9][10][11][12] , 29D12 [5][6][7][8][9][10][11][12] , 13G12 [13][14][15][16][17][18][19][20] , 21E3 [13][14][15][16][17][18][19][20][21][22][23][24] , 1D4 [13][14][15][16][17][18][19][20][21][22][23][24] , 16F3 [13][14][15]…”

Section: Recombinant Proteins and Monoclonal Antibodiesunclassified

“…Recently, we have demonstrated that NT-proBNP in human blood is also glycosylated and that glycosylation negatively influences the recognition of NT-proBNP by antibodies specific to the central part of the molecule (5 ). For several years, 2 proprotein convertases, furin and corin, have been discussed in the literature as possible candidates responsible for proBNP processing (10,11 ), but the question of which of these 2 enzymes (and possibly other convertases) is responsible for proBNP processing in cardiomyocytes remains unanswered.…”

Section: Probnp Processing Is Suppressed By O-glycosylationmentioning

confidence: 99%

“…NT-proBNP and proBNP from HF patient plasma and recombinant proteins produced in different cell lines were analyzed with 11 2-site MAb combinations. The capture antibodies, which were the same in all assays and were specific to different epitopes, covered the entire NTproBNP molecule (29D12 [5][6][7][8][9][10][11][12] , 21E3 [13][14][15][16][17][18][19][20] , 1D4 13-24 , 5D3 28-45 , 11D1 31-39 , 16E6 34 -39 , 16D10 46 -56 , 15C4 63-71 , 21E6 67-73 , 24E11 [67][68][69][70][71][72][73][74][75][76] , and 28F8 67-76 ). In proBNP assays, MAb 24C5 87-98 was used as the detection antibody to form pairs with the above-mentioned capture MAbs.…”

Section: Sandwich 2-step Immunofluorescence Assaymentioning

confidence: 99%

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Processing of Pro–Brain Natriuretic Peptide Is Suppressed by O-Glycosylation in the Region Close to the Cleavage Site

et al. 2009

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Background: Processing of the brain natriuretic peptide (BNP) precursor, proBNP, is a convertase-dependent reaction that produces 2 molecules—the active BNP hormone and the N-terminal part of proBNP (NT-proBNP). Although proBNP was first described more than 15 years ago, very little is known about the cellular mechanism of its processing. The study of proBNP processing mechanisms is important, because processing impairments could be associated with the development of heart failure (HF). Methods: The biochemical properties of recombinant proBNP and NT-proBNP and the same molecules derived from the blood of HF patients were analyzed by gel-filtration chromatography, site-directed mutagenesis, and different immunochemical methods with a panel of monoclonal antibodies (MAbs). Results: Part of the proBNP molecule (amino acid residues 61–76) located near the cleavage site was inaccessible to specific MAbs because of the presence of O-glycans, whereas the same region in NT-proBNP was completely accessible. We demonstrated that a convertase (furin) could effectively cleave deglycosylated (but not intact) proBNP. Of several mutant proBNP forms produced in a HEK 293 cell line, only the T71A variant was effectively processed in the cell. Conclusions: Only proBNP that was not glycosylated in the region of the cleavage site could effectively be processed into BNP and NT-proBNP. Site-directed mutagenesis enabled us to ascertain the unique suppressing role of T71-bound O-glycan in proBNP processing.

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“…The former exhibits the biological activity, whereas no defined biological function has been found to be associated with the latter. The processing site in proBNP occurs immediately downstream from the Arg 73 -X-X-Arg 76 sequence, at a cleavage site similar to that recognized by the ubiquitous endoprotease furin (7,8 ). However, other endoproteases, such as corin (9,10 ), or prohormone convertases (11 ) may be involved in the posttranslational maturation of proBNP .…”

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confidence: 99%

Assay for Measurement of Intact B-Type Natriuretic Peptide Prohormone in Blood

et al. 2006

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Background: B-Type natriuretic peptide (BNP 1-32 ) as well as the N-terminal fragment of the prohormone containing residues 1-76 (NT-proBNP 1-76 ), both cleavage products of the precursor proBNP 1-108 , are reported to be powerful markers for prognosis and risk stratification of heart failure. However, the intact precursor also circulates in the bloodstream. Assays for the detection of these cleavage products have been developed, but most of these assays may overestimate the concentrations of the cleavage products because they also measure the precursor form. It is therefore important to develop an immunoassay that specifically measures solely proBNP 1-108 in plasma. Methods: After carefully designing the peptide used to immunize mice, we selected a specific monoclonal antibody (mAb Hinge76) that recognizes the cleavage site of proBNP 1-108 , an epitope present only in the precursor form. mAb Hinge76 recognizes recombinant proBNP 1-108 in a dose-dependent manner, without any significant cross-reactivity with either recombinant NT-proBNP 1-76 or synthetic BNP 1-32 . By combining mAb Hinge76 with a polyclonal antibody directed against BNP 1-32 , we were able to set up a proBNP 1-108 -specific sandwich immunoassay able to confirm the presence of proBNP 1-108 in blood samples. Results: From a cohort of 50 healthy persons and 170 patients with congestive heart failure (CHF), our assay was able to differentiate healthy individuals from CHF patients (P <0.005). Interestingly, plasma proBNP 1-108

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Stretch-induced Hypertrophic Growth of Cardiocytes and Processing of Brain-type Natriuretic Peptide Are Controlled by Proprotein-processing Endoprotease Furin

Cited by 122 publications

References 74 publications

Novel cardiac peptide hormone in several teleosts

Novel cardiac peptide hormone in several teleosts

Processing of Pro–Brain Natriuretic Peptide Is Suppressed by O-Glycosylation in the Region Close to the Cleavage Site

Assay for Measurement of Intact B-Type Natriuretic Peptide Prohormone in Blood

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