title: Stretch-induced hypertrophic growth of cardiocytes and processing of brain-type natriuretic peptide are controlled by proprotein-processing endoprotease furin.
abstract: When hypertrophic growth is induced in neonatal rat cardiocytes by stretching, the cardiocytes express high levels of brain-type natriuretic peptide (BNP) and the proprotein-processing enzyme furin. A BNP precursor, gammaBNP, possesses a furin-cleavable Arg-X-X-Arg motif, which is cleaved when gammaBNP is processed to form BNP-45. The Arg-X-X-Arg motif is found in many precursors of growth factors and growth-related proteins. To determine if furin converts gammaBNP to BNP-45 as well as other unidentified growth-promoting protein precursors to their active form that may induce hypertrophic growth in cardiocytes, we used two protease inhibitor systems, synthetic peptidyl chloromethyl ketones (CMK) (dec-Arg-Val-Lys-Arg-CMK and dec-Phe-Ala-Lys-Arg-CMK; where dec is decanoyl) and vaccinia vector-integrated native and variant alpha1-antitrypsins. The furin-specific inhibitors, dec-Arg-Val-Lys-Arg-CMK and variant alpha1-antitrypsin with the inhibitory determinant Arg-X-X-Arg, suppressed the stretch-induced hypertrophic growth of cardiocytes as well as the processing of gammaBNP to BNP-45. The other serine protease inhibitors and variant alpha1-antitrypsin against elastase, or thrombin, however, neither suppressed the hypertrophic growth nor prevented the processing of gammaBNP to BNP-45. Thus, we suggest that furin catalyzes the conversion of gammaBNP to BNP-45 as well as growth-promoting proproteins to their active form, which might induce hypertrophic growth in cardiocytes.
authors.affiliation: Department of Molecular Medicine, Gunma University School of Medicine, Maebashi 371, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Sawada
authors.forename: M
authors.initials: M
authors.lastname: Suda
authors.forename: H
authors.initials: H
authors.lastname: Yokoyama
authors.forename: T
authors.initials: T
authors.lastname: Kanda
authors.forename: T
authors.initials: T
authors.lastname: Sakamaki
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: R
authors.initials: R
authors.lastname: Nagai
authors.forename: S
authors.initials: S
authors.lastname: Abe
authors.forename: T
authors.initials: T
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000209:etiology*; D002478:Cells, Cultured; D045683:Furin; D020097:Natriuretic Peptide, Brain; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013381:Subtilisins / Q000502:physiology*
chemical_list: D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D020097:Natriuretic Peptide, Brain; D013381:Subtilisins; D045683:Furin