Doxorubicin induces de novo expression of N-terminal-truncated matrix metalloproteinase-2 in cardiac myocytes
| Autor: | Bryan G. Hughes, Andrej Roczkowsky, Ramses Ilarraza, Nils Moser, Richard Schulz, Mathieu Poirier, Brandon Y H Chan |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Gene isoform Physiology Down-Regulation 030204 cardiovascular system & hematology Matrix metalloproteinase Hydroxamic Acids medicine.disease_cause Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Physiology (medical) Troponin I medicine Animals Myocyte Actinin Myocytes Cardiac Doxorubicin RNA Messenger Sulfones Aconitate Hydratase Pharmacology Chemistry Phenyl Ethers General Medicine Rats Up-Regulation Cell biology Oxidative Stress 030104 developmental biology Matrix Metalloproteinase 2 Intracellular Oxidative stress medicine.drug |
| Zdroj: | Canadian Journal of Physiology and Pharmacology. 96:1238-1245 |
| ISSN: | 1205-7541 0008-4212 |
| DOI: | 10.1139/cjpp-2018-0275 |
| Popis: | Anthracyclines, such as doxorubicin, are commonly prescribed antineoplastic agents that cause irreversible cardiac injury. Doxorubicin cardiotoxicity is initiated by increased oxidative stress in cardiomyocytes. Oxidative stress enhances intracellular matrix metalloproteinase-2 (MMP-2) by direct activation of its full-length isoform and (or) de novo expression of an N-terminal-truncated isoform (NTT-MMP-2). As MMP-2 is localized to the sarcomere, we tested whether doxorubicin activates intracellular MMP-2 in neonatal rat ventricular myocytes (NRVM) and whether it thereby proteolyzes two of its identified sarcomeric targets, α-actinin and troponin I. Doxorubicin increased oxidative stress within 12 h as indicated by reduced aconitase activity. This was associated with a twofold increase in MMP-2 protein levels and threefold higher gelatinolytic activity. MMP inhibitors ARP-100 or ONO-4817 (1 μM) prevented doxorubicin-induced MMP-2 activation. Doxorubicin also increased the levels and activity of MMP-2 secreted into the conditioned media. Doxorubicin upregulated the mRNA expression of both full-length MMP-2 and NTT-MMP-2. α-Actinin levels remained unchanged, whereas doxorubicin downregulated troponin I in an MMP-independent manner. Doxorubicin induces oxidative stress and stimulates a robust increase in MMP-2 expression and activity in NRVM, including NTT-MMP-2. The sarcomeric proteins α-actinin and troponin I are, however, not targeted by MMP-2 under these conditions. |
| Databáze: | OpenAIRE |
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