Matrix metalloproteinase-2 and -9 are induced differently by doxorubicin in H9c2 cells: The role of MAP kinases and NAD(P)H oxidase

Paolo Spallarossa, Paola Altieri, Silvano Garibaldi, Giorgio Ghigliotti, Chiara Barisione, Valeria Manca, Patrizia Fabbi, Alberto Ballestrero, Claudio Brunelli, Antonio Barsotti

Research output: Contribution to journalArticle

Abstract

Objective: Dysregulation of myocardial metalloproteinases (MMPs) is now regarded as an early contributory mechanism for the initiation and progression of heart failure. Doxorubicin is a strongly cardiotoxic anticancer drug. This study investigates the effects of doxorubicin on myocardial MMP-2 and MMP-9 activation. Methods: After pre-treatment with or without carvedilol or dexrazoxane, we exposed H9c2 cardiomyocytes to doxorubicin to evaluate reactive oxygen species (ROS) formation and MMP-2 and MMP-9 expression and activation. To investigate the signaling pathways leading to doxorubicin-induced MMP activation, we also examined the phosphorylation of three members of the MAPK family (ERK1/2, p38, and JNK), the effects of selective inhibitors of ERK1/2, p38, and JNK on MMP transcription and activity, the transcription of the NAD(P)H oxidase subunit Nox1, and the effects of the NAD(P)H oxidase inhibitor DPI on MMP activation. Results: Doxorubicin induces a significant increase in ROS formation and a rapid increase of MMP expression and activation. Pre-treatment with carvedilol or dexrazoxane prevented these effects. We also found that p38 is the MAPK that is mainly responsible for MMP-9 activation through an NAD(P)H-independent mechanism. ERK and JNK modulate the transcription of the NAD(P)H oxidase subunit Nox1, while the JNK/ERK NAD(P)H oxidase cascade is an important pathway that mediates doxorubicin signaling to MMP-2. Inhibition of NAD(P)H oxidase attenuates the increase in MMP-2, but augments the doxorubicin-induced increase in MMP-9. Conclusions: Enhancement of MMP-2 and MMP-9 in cardiac myocytes in response to doxorubicin is mediated by the cooperation of ERK, JNK, and p38 kinase pathways, most of which are redox dependent.

Original languageEnglish
Pages (from-to)736-745
Number of pages10
JournalCardiovascular Research
Volume69
Issue number3
DOIs
Publication statusPublished - Feb 15 2006

Keywords

  • MAP kinase
  • Matrix metalloproteinases
  • Myocytes
  • NADPH oxidase
  • Oxygen radicals

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Spallarossa, P., Altieri, P., Garibaldi, S., Ghigliotti, G., Barisione, C., Manca, V., Fabbi, P., Ballestrero, A., Brunelli, C., & Barsotti, A. (2006). Matrix metalloproteinase-2 and -9 are induced differently by doxorubicin in H9c2 cells: The role of MAP kinases and NAD(P)H oxidase. Cardiovascular Research, 69(3), 736-745. https://doi.org/10.1016/j.cardiores.2005.08.009