title: 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.affiliation: 1 Division of Health Sciences, Department of Molecular Pathology, Osaka University Graduate School of Medicine , Suita, Japan .
authors.forename: Ayako
authors.initials: A
authors.lastname: Uchinaka
authors.forename: Naomasa
authors.initials: N
authors.lastname: Kawaguchi
authors.forename: Seiji
authors.initials: S
authors.lastname: Mori
authors.forename: Yoshinosuke
authors.initials: Y
authors.lastname: Hamada
authors.forename: Shigeru
authors.initials: S
authors.lastname: Miyagawa
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Saito
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
authors.forename: Nariaki
authors.initials: N
authors.lastname: Matsuura
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002316:Cardiotonic Agents / Q000008:administration & dosage; D004343:Drug Implants / Q000008:administration & dosage*; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000008:administration & dosage*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000008:administration & dosage*; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D002316:Cardiotonic Agents; D004343:Drug Implants; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3