Copyright © 2005, European Society of Cardiology
Matrix metalloproteinase-2 and -9 are induced differently by doxorubicin in H9c2 cells: The role of MAP kinases and NAD(P)H oxidase
aResearch Center of Cardiovascular Biology, Department of Cardiology, University of Genova, Viale Benedetto XV, 6 16132 Genova, Italy
bDepartment of Internal Medicine, University of Genova, 16132 Genova, Italy
* Corresponding author. Tel.: +39 0103537990; fax: +39 0103538655. Email address: paola.altieri{at}unige.it
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.
KEYWORDS Matrix metalloproteinases; Myocytes; MAP kinase; NADPH oxidase; Oxygen radicals
1 Both authors contributed equally to this study.
Time for primary review 9 days
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