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Cited by 182Chemotherapy-induced cardiotoxicity and mitigationProtease and Inhibitor MechanismsCardiac Fibrosis and Remodeling

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

SPALLAROSSA, P, ALTIERI, P, GARIBALDI, S, GHIGLIOTTI, G, BARISIONE, C, MANCA, V, FABBI, P, BALLESTRERO, A +2 more·2006·Cardiovascular Research
DOI 10.1016/j.cardiores.2005.08.009
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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.

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Crossref · 10.1016/j.cardiores.2005.08.009

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  • Tyrosines for which the aromatic ring is closer to the surface of a protein, in which there is a neighboring negative charge, and those in hydrophobic regions are more likely to be nitrated.

    “Tyrosines for which the aromatic ring is closer to the surface of a protein, in which there is a neighboring negative charge, and those in hydrophobic regions are more likely to be nitrated (66, 877).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [877]

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Authors
SPALLAROSSA, P., ALTIERI, P., GARIBALDI, S., GHIGLIOTTI, G., BARISIONE, C., MANCA, V, FABBI, P., BALLESTRERO, A., BRUNELLI, C., & BARSOTTI, A.
Affiliations
University of Genoa (IT)
Corresponding author
ALTIERI, P
ORCID
Venue
Cardiovascular Research
Publisher
Oxford University Press (OUP)
Published
2006-02-15
Volume
69
Issue
3
Pages
736-745
ISSN
0008-6363 (ISSN-L)
DOI
10.1016/j.cardiores.2005.08.009
OpenAlex
W2153709731
Cited by
182
References
44
Citations by year
2026: 1 · 2025: 9 · 2024: 6 · 2023: 15 · 2022: 7 · 2021: 11 · 2020: 6 · 2019: 7 · 2018: 12 · 2017: 11 · 2016: 8 · 2015: 10 · 2014: 11 · 2013: 11 · 2012: 9
FWCI
4.34
Type
journal article
Language
en
Open access
closed
Locations
  • Cardiovascular Research (publishedVersion)
  • PubMed (publishedVersion)
  • CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Chemotherapy-induced cardiotoxicity and mitigation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
doxorubicin, cardiotoxicity, MMP-2, MMP-9, MAPK signaling, p38 MAPK, ERK1/2, JNK, NADPH oxidase, NOX1, reactive oxygen species, carvedilol, dexrazoxane, H9c2 cells, heart failure, redox signaling
MeSH terms
Carvedilol, Anthracenes, Antibiotics, Antineoplastic, Antioxidants, Carbazoles, Catecholamines, Cell Line, Doxorubicin, Enzyme Activation, Flavonoids, Humans, Imidazoles, Propanolamines, Protein-Tyrosine Kinases, Pyridines, Razoxane, Blotting, Western, NADPH Oxidases, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Matrix Metalloproteinases, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Myocytes, Cardiac, p38 Mitogen-Activated Protein Kinases, Imidazolines, Janus Kinase 1

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