title: Matrix metalloproteinase-2 in oncostatin M-induced sarcomere degeneration in cardiomyocytes.
abstract: Cardiomyocyte dedifferentiation may be an important source of proliferating cardiomyocytes facilitating cardiac repair. Cardiomyocyte dedifferentiation and proliferation induced by oncostatin-M (OSM) is characterized by sarcomere degeneration. However, the mechanism underlying sarcomere degeneration remains unclear. We hypothesized that this process may involve matrix metalloproteinase-2 (MMP-2), a key protease localized at the sarcomere in cardiomyocytes. We tested the hypothesis that MMP-2 is involved in the sarcomere degeneration that characterizes cardiomyocyte dedifferentiation. Confocal immunofluorescence and biochemical methods were used to explore the role of MMP-2 in OSM-induced dedifferentiation of neonatal rat ventricular myocytes (NRVM). OSM caused a concentration- and time-dependent loss of sarcomeric α-actinin and troponin-I in NRVM. Upon OSM-treatment, the mature sarcomere transformed to a phenotype resembling a less-developed sarcomere, i.e., loss of sarcomeric proteins and Z-disk transformed into disconnected Z bodies, characteristic of immature myofibrils. OSM dose dependently increased MMP-2 activity. Both the pan-MMP inhibitor GM6001 and the selective MMP-2 inhibitor ARP 100 prevented sarcomere degeneration induced by OSM treatment. OSM also induced NRVM cell cycling and increased methyl-thiazolyl-tetrazolium (MTT) staining, preventable by MMP inhibition. These results suggest that MMP-2 mediates sarcomere degeneration in OSM-induced cardiomyocyte dedifferentiation and thus potentially contributes to cardiomyocyte regeneration.
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Canada; and Department of Pharmacology, University of Alberta, Edmonton, Canada.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Canada; and Department of Pharmacology, University of Alberta, Edmonton, Canada.
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Hughes
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Canada; and Department of Pharmacology, University of Alberta, Edmonton, Canada.
authors.forename: Mohammad A M
authors.initials: MA
authors.lastname: Ali
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Canada; and Department of Pharmacology, University of Alberta, Edmonton, Canada.
authors.forename: Brandon Y H
authors.initials: BY
authors.lastname: Chan
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Canada; and Department of Pharmacology, University of Alberta, Edmonton, Canada.
authors.forename: Katherine
authors.initials: K
authors.lastname: Launier
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Canada; and Department of Pharmacology, University of Alberta, Edmonton, Canada richard.schulz@ualberta.ca.
authors.forename: Richard
authors.initials: R
authors.lastname: Schulz
mesh_terms: D000185:Actinin / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D054337:Cell Dedifferentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D053683:Oncostatin M / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D012518:Sarcomeres / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013997:Time Factors; D019210:Troponin I / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D019210:Troponin I; D053683:Oncostatin M; D000185:Actinin; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat
keywords: cardiomyocytes; dedifferentiation; matrix metalloproteinase-2; oncostatin-M; sarcomere