title: SVVYGLR motif of the thrombin-cleaved N-terminal osteopontin fragment enhances the synthesis of collagen type III in myocardial fibrosis.
abstract: Osteopontin (OPN) is involved in various physiological processes such as inflammatory and wound healing. However, little is known about the effects of OPN on these tissues. OPN is cleaved by thrombin, and cleavage of the N-terminal fragment exposes a SVVYGLR sequence on its C-terminus. In this study, we examined the effects of the thrombin-cleaved OPN fragments on fibroblasts and myocardial fibrosis, particularly the role of the SVVYGLR sequence. The recombinant thrombin-cleaved OPN fragments (N-terminal fragment [N-OPN], C-terminal fragment [C-OPN], and the N-terminal fragment lacking the SVVYGLR sequence [ΔSV N-OPN]) were added to fibroblasts, and the cellular motility, signal activity, and production of collagen were evaluated. A sustained-release gel containing an OPN fragment or SVVYGLR peptide was transplanted into a rat model of ischemic cardiomyopathy and the quantities and ratio of collagen type I (COL I) and type III (COL III) were estimated. N-OPN significantly promoted fibroblast migration. Smad signal activity, expression of smooth muscle actin (SMA), and the production of COL III were enhanced by N-OPN and SVVYGLR peptide. Conversely, ΔSV N-OPN and C-OPN had no effect. In vivo, the expression level of N-OPN was associated with COL III distribution, and the COL III/COL I ratio was significantly increased by the sustained-release gel containing N-OPN or SVVYGLR peptide. The cardiac function was also significantly improved by the N-OPN- or SVVYGLR peptide-released gel treatment. The N-terminal fragment of thrombin-cleaved OPN-induced Smad signal activation, SMA expression, and COL III production, and its SVVYGLR sequence influences this function.
authors.affiliation: Division of Health Sciences, Department of Cardiovascular Pathology, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Uchinaka
authors.affiliation: Division of Health Sciences, Department of Cardiovascular Pathology, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yoshinosuke
authors.initials: Y
authors.lastname: Hamada
authors.affiliation: Division of Health Sciences, Department of Molecular Pathology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Mori
authors.affiliation: Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Miyagawa
authors.affiliation: Medical Center of Translational Research, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Saito
authors.affiliation: Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
authors.affiliation: Division of Health Sciences, Department of Molecular Pathology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Nariaki
authors.initials: N
authors.lastname: Matsuura
authors.affiliation: Division of Health Sciences, Department of Molecular Pathology, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Division of Health Sciences, Department of Cardiovascular Pathology, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita, Osaka, 565-0871, Japan. kawaguch@sahs.med.osaka-u.ac.jp.
authors.forename: Naomasa
authors.initials: N
authors.lastname: Kawaguchi
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000503:physiopathology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D024061:Collagen Type III / Q000378:metabolism*; D003692:Delayed-Action Preparations; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D009842:Oligopeptides / Q000008:administration & dosage* / Q000494:pharmacology; D053495:Osteopontin / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000166:cytology* / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism
chemical_list: D024061:Collagen Type III; D003692:Delayed-Action Preparations; D009842:Oligopeptides; C586051:SVVYGLR peptide; D053495:Osteopontin; D013917:Thrombin
keywords: Collagen type III; Fibrosis; Osteopontin; SVVYGLR peptide