Tissue inhibitor of metalloproteinase-1 and -3 improves cardiac function in an ischemic cardiomyopathy model rat.

Abstract

Matrix metalloproteinases (MMPs) and a family of tissue inhibitors of metalloproteinases (TIMPs) may contribute to myocardial remodeling in heart failure. TIMPs are the main inhibitors of MMPs and have other MMP-independent functions. Because little is known of the role of TIMPs in the heart, we examined the effects of TIMPs on cardiac fibroblasts (CFs) and cardiomyocytes. In vitro, TIMP-1-4 enhanced smooth muscle actin (SMA) expression in CFs, and TIMP-1 and TIMP-3 enhanced the expression of phosphorylated Smad-3 and phosphorylated transforming growth factor (TGF)-β type 1 receptor in CFs; this effect was inhibited by TGF-β receptor blocker SB-505124. TIMPs-1, -3, and -4 also inhibited the FAK, AKT, and ERK pathways that induce cardiac hypertrophy. TIMP-1 and TIMP-2 suppressed apoptosis in cardiomyocytes; in contrast, TIMP-4 induced apoptosis in CFs. TIMP-2 stimulated collagen synthesis. Collagen gels containing TIMP-1 or TIMP-3, which exhibit cardioprotective effects in vitro, were transplanted to the left ventricular anterior wall of a rat heart model of myocardial infarction. Gel-released TIMP-1 and TIMP-3 significantly improved cardiac function and myocardial remodeling and enhanced SMA expression in the infarcted area in ischemic cardiomyopathy model rats. Further, the transplantation of TIMP-1 or TIMP-3 gels inhibited apoptosis in the ischemic myocardium and reduced MMP-2 activity. TIMPs may be an ideal target of cardiac regeneration therapy.

• Authors: Ayako Uchinaka, Naomasa Kawaguchi, Seiji Mori, Yoshinosuke Hamada, Shigeru Miyagawa, Atsuhiro Saito, Yoshiki Sawa, Nariaki Matsuura
• Journal: Tissue engineering. Part A (Tissue Eng Part A) Vol. 20 Issue 21-22 Pg. 3073-84 (Nov 2014) ISSN: 1937-335X [Electronic] United States
• PMID: 24814095 (Publication Type: Journal Article)

Chemical References

• Cardiotonic Agents
• Drug Implants
• Tissue Inhibitor of Metalloproteinase-1
• Tissue Inhibitor of Metalloproteinase-3

Topics

• Animals
• Cardiomyopathies (complications, drug therapy, pathology)
• Cardiotonic Agents (administration & dosage)
• Drug Implants (administration & dosage)
• Male
• Myocardial Ischemia (complications, drug therapy, pathology)
• Rats
• Rats, Sprague-Dawley
• Recovery of Function (drug effects)
• Tissue Inhibitor of Metalloproteinase-1 (administration & dosage)
• Tissue Inhibitor of Metalloproteinase-3 (administration & dosage)
• Treatment Outcome
• Ventricular Remodeling (drug effects)