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MMP inhibitors attenuate doxorubicin cardiotoxicity by preventing intracellular and extracellular matrix remodelling.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2021 Jan 01; Vol. 117 (1), pp. 188-200. - Publication Year :
- 2021
-
Abstract
- Aims: Heart failure is a major complication in cancer treatment due to the cardiotoxic effects of anticancer drugs, especially from the anthracyclines such as doxorubicin (DXR). DXR enhances oxidative stress and stimulates matrix metalloproteinase-2 (MMP-2) in cardiomyocytes. We investigated whether MMP inhibitors protect against DXR cardiotoxicity given the role of MMP-2 in proteolyzing sarcomeric proteins in the heart and remodelling the extracellular matrix.<br />Methods and Results: Eight-week-old male C57BL/6J mice were treated with DXR weekly with or without MMP inhibitors doxycycline or ONO-4817 by daily oral gavage for 4 weeks. Echocardiography was used to determine cardiac function and left ventricular remodelling before and after treatment. MMP inhibitors ameliorated DXR-induced systolic and diastolic dysfunction by reducing the loss in left ventricular ejection fraction, fractional shortening, and E'/A'. MMP inhibitors attenuated adverse left ventricular remodelling, reduced cardiomyocyte dropout, and prevented myocardial fibrosis. DXR increased myocardial MMP-2 activity in part also by upregulating N-terminal truncated MMP-2. Immunogold transmission electron microscopy showed that DXR elevated MMP-2 levels within the sarcomere and mitochondria which were associated with myofilament lysis, mitochondrial degeneration, and T-tubule distention. DXR-induced myofilament lysis was associated with increased titin proteolysis in the heart which was prevented by ONO-4817. DXR also increased the level and activity of MMP-2 in human embryonic stem cell-derived cardiomyocytes, which was reduced by ONO-4817.<br />Conclusions: MMP-2 activation is an early event in DXR cardiotoxicity and contributes to myofilament lysis by proteolyzing cardiac titin. Two orally available MMP inhibitors ameliorated DXR cardiotoxicity by attenuating intracellular and extracellular matrix remodelling, suggesting their use may be a potential prophylactic strategy to prevent heart injury during chemotherapy.<br /> (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Animals
Cardiotoxicity
Cell Line
Disease Models, Animal
Doxorubicin
Extracellular Matrix enzymology
Extracellular Matrix pathology
Fibrosis
Heart Diseases chemically induced
Heart Diseases enzymology
Heart Diseases physiopathology
Human Embryonic Stem Cells drug effects
Human Embryonic Stem Cells enzymology
Humans
Male
Mice, Inbred C57BL
Mitochondria, Heart drug effects
Mitochondria, Heart enzymology
Mitochondria, Heart ultrastructure
Myocytes, Cardiac enzymology
Myocytes, Cardiac ultrastructure
Protein Kinases metabolism
Proteolysis
Mice
Doxycycline pharmacology
Extracellular Matrix drug effects
Heart Diseases prevention & control
Matrix Metalloproteinase 2 metabolism
Matrix Metalloproteinase Inhibitors pharmacology
Myocytes, Cardiac drug effects
Phenyl Ethers pharmacology
Ventricular Function, Left drug effects
Ventricular Remodeling drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 117
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 31995179
- Full Text :
- https://doi.org/10.1093/cvr/cvaa017