Ayako Uchinaka1, Maho Yoshida2, Kiyoka Tanaka2, Yoshinosuke Hamada3, Seiji Mori4, Yoshitaka Maeno5, Shigeru Miyagawa6, Yoshiki Sawa6, Kohzo Nagata1, Hirofumi Yamamoto3, Naomasa Kawaguchi7. 1. Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Aichi, Japan. 2. Division of Health Sciences, Department of Cardiovascular Pathology, Osaka University Graduate School of Medicine, Osaka, Japan. 3. Division of Health Sciences, Department of Molecular Pathology, Osaka University Graduate School of Medicine, Osaka, Japan. 4. Division of Health Sciences, Department of Molecular Pathology, Osaka University Graduate School of Medicine, Osaka, Japan; Department of Medical Technology, Faculty of Health Sciences, Morinomiya University of Medical Sciences, Osaka, Japan. 5. Department of Food and Nutritional Sciences, Collage of Bioscience and Biotechnology, Chubu University, Aichi, Japan. 6. Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan. 7. Division of Health Sciences, Department of Cardiovascular Pathology, Osaka University Graduate School of Medicine, Osaka, Japan; Department of Drug Discovery Cardiovascular Regeneration, Osaka University Graduate School of Medicine, Osaka, Japan. Electronic address: kawaguch@sahs.med.osaka-u.ac.jp.
Abstract
OBJECTIVE: Left ventricular (LV) remodeling alters the contractile and relaxation properties and induces myocardial stiffness. As LV remodeling progresses, the amount of collagen type III (Col3) is gradually decreased, being replaced by collagen type I (Col1). We evaluated whether Col3 overexpression improved cardiac function and remodeling in a rat with ischemic cardiomyopathy (ICM). We also investigated the functional motif and mechanism of thrombin-cleaved N-terminal osteopontin (N-OPN) on cardiac remodeling. METHODS: The rats with ICM were divided into 3 groups: ligation only (Control) group and groups transplanted with nontransfected fibroblast sheets (normal Fb group) or with Col3-secretory fibroblast sheets (Col3 Fb group). A gelatin hydrogel containing the N-terminal fragment (N-OPN), N-OPN lacking the SVVYGLR sequence (⊿SV), the Arg-Gly-Asp (RGD) sequence (⊿RGD), RGD and SVVYGLR sequences (⊿RGD-SV), SVVYGLR alone (SV), or a random SV peptide was implanted into an ICM model rat. RESULTS: The Col3 Fb group exhibited significantly attenuated LV systolic dysfunction. LV dilatation, myocyte hypertrophy, and LV fibrosis at the infarcted area were also attenuated by Col3 Fb implantation. Furthermore, N-OPN, ⊿RGD, and SV peptide suppressed the depression of cardiac function, LV dilatation, and myocyte hypertrophy, and also induced increased Col3 expression and reduction in the ratio of Col1 to Col3 in the infarcted and border areas. CONCLUSIONS: Overexpression of Col3 improved cardiac function by changing the balance of collagen distribution in LV remodeling. The SVVYGLR motif of the thrombin-cleaved N-OPN and SV peptide attenuated cardiac dysfunction by increasing Col3 and changing the pattern of collagen balance in the impaired area.
OBJECTIVE: Left ventricular (LV) remodeling alters the contractile and relaxation properties and induces myocardial stiffness. As LV remodeling progresses, the amount of collagen type III (Col3) is gradually decreased, being replaced by collagen type I (Col1). We evaluated whether Col3 overexpression improved cardiac function and remodeling in a rat with ischemic cardiomyopathy (ICM). We also investigated the functional motif and mechanism of thrombin-cleaved N-terminal osteopontin (N-OPN) on cardiac remodeling. METHODS: The rats with ICM were divided into 3 groups: ligation only (Control) group and groups transplanted with nontransfected fibroblast sheets (normal Fb group) or with Col3-secretory fibroblast sheets (Col3 Fb group). A gelatin hydrogel containing the N-terminal fragment (N-OPN), N-OPN lacking the SVVYGLR sequence (⊿SV), the Arg-Gly-Asp (RGD) sequence (⊿RGD), RGD and SVVYGLR sequences (⊿RGD-SV), SVVYGLR alone (SV), or a random SV peptide was implanted into an ICM model rat. RESULTS: The Col3 Fb group exhibited significantly attenuated LV systolic dysfunction. LV dilatation, myocyte hypertrophy, and LV fibrosis at the infarcted area were also attenuated by Col3 Fb implantation. Furthermore, N-OPN, ⊿RGD, and SV peptide suppressed the depression of cardiac function, LV dilatation, and myocyte hypertrophy, and also induced increased Col3 expression and reduction in the ratio of Col1 to Col3 in the infarcted and border areas. CONCLUSIONS: Overexpression of Col3 improved cardiac function by changing the balance of collagen distribution in LV remodeling. The SVVYGLR motif of the thrombin-cleaved N-OPN and SV peptide attenuated cardiac dysfunction by increasing Col3 and changing the pattern of collagen balance in the impaired area.
Authors: Stephanie Zalesak-Kravec; Weiliang Huang; Pengcheng Wang; Jianshi Yu; Tian Liu; Amy E Defnet; Alexander R Moise; Ann M Farese; Thomas J MacVittie; Maureen A Kane Journal: Health Phys Date: 2021-10-01 Impact factor: 2.922