Overexpression of collagen type III in injured myocardium prevents cardiac systolic dysfunction by changing the balance of collagen distribution.

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.

• Authors: Ayako Uchinaka, Maho Yoshida, Kiyoka Tanaka, Yoshinosuke Hamada, Seiji Mori, Yoshitaka Maeno, Shigeru Miyagawa, Yoshiki Sawa, Kohzo Nagata, Hirofumi Yamamoto, Naomasa Kawaguchi
• Journal: The Journal of thoracic and cardiovascular surgery (J Thorac Cardiovasc Surg) Vol. 156 Issue 1 Pg. 217-226.e3 (07 2018) ISSN: 1097-685X [Electronic] United States
• PMID: 29551535 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Chemical References

• COL3A1 protein, human
• Collagen Type I
• Collagen Type III
• Peptide Fragments
• SPP1 protein, human
• Osteopontin

Topics

• Animals
• Cardiomyopathies (genetics, metabolism, physiopathology, surgery)
• Cell- and Tissue-Based Therapy (methods)
• Cells, Cultured
• Collagen Type I (metabolism)
• Collagen Type III (genetics, metabolism)
• Disease Models, Animal
• Fibroblasts (metabolism, transplantation)
• Genetic Therapy (methods)
• Male
• Myocardium (metabolism, pathology)
• Osteopontin (pharmacology)
• Peptide Fragments (pharmacology)
• Rats, Inbred Lew
• Systole
• Ventricular Function, Left
• Ventricular Remodeling