Dataset Information

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase-induced cardiomyopathy: involvement of mitofusin-2.

ABSTRACT:

Background and purpose

The anthracycline doxorubicin (DOX), although successful as a first-line cancer treatment, induces cardiotoxicity linked with increased production of myocardial ROS, with Nox2 NADPH oxidase-derived superoxide reported to play a key role. The aim of this study was to identify novel mechanisms underlying development of cardiac remodelling/dysfunction further to DOX-stimulated Nox2 activation.

Experimental approach

Nox2^-/- and wild-type (WT) littermate mice were administered DOX (12 mg·kg^-1 over 3 weeks) prior to study at 4 weeks. Detailed mechanisms were investigated in murine HL-1 cardiomyocytes, employing a robust model of oxidative stress, gene silencing and pharmacological tools.

Key results

DOX-induced cardiac dysfunction, cardiomyocyte remodelling, superoxide production and apoptosis in WT mice were attenuated in Nox2^-/- mice. Transcriptional analysis of left ventricular tissue identified 152 differentially regulated genes (using adjusted P < 0.1) in DOX-treated Nox2^-/- versus WT mice, and network analysis highlighted 'Cell death and survival' as the biological function most significant to the dataset. The mitochondrial membrane protein, mitofusin-2 (Mfn2), appeared as a strong candidate, with increased expression (1.5-fold), confirmed by qPCR (1.3-fold), matching clear published evidence of promotion of cardiomyocyte cell death. In HL-1 cardiomyocytes, targeted siRNA knockdown of Nox2 decreased Mfn2 protein expression, but not vice versa. While inhibition of Nox2 activity along with DOX treatment attenuated its apoptotic and cytotoxic effects, reduced apoptosis after Mfn2 silencing reflected a sustained cytotoxic response and reduced cell viability.

Conclusions and implications

DOX-induced and Nox2-mediated up-regulation of Mfn2, rather than contributing to cardiomyocyte dysfunction through apoptotic pathways, appears to promote a protective mechanism.

Linked articles

This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc.

SUBMITTER: McLaughlin D

PROVIDER: S-EPMC5647180 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Publications

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase-induced cardiomyopathy: involvement of mitofusin-2.

McLaughlin Declan D Zhao Youyou Y O'Neill Karla M KM Edgar Kevin S KS Dunne Philip D PD Kearney Anna M AM Grieve David J DJ McDermott Barbara J BJ

British journal of pharmacology 20170422 21

<h4>Background and purpose</h4>The anthracycline doxorubicin (DOX), although successful as a first-line cancer treatment, induces cardiotoxicity linked with increased production of myocardial ROS, with Nox2 NADPH oxidase-derived superoxide reported to play a key role. The aim of this study was to identify novel mechanisms underlying development of cardiac remodelling/dysfunction further to DOX-stimulated Nox2 activation.<h4>Experimental approach</h4>Nox2<sup>-/-</sup> and wild-type (WT) litterma ...[more]

PMID: 28261787

Similar Datasets

Project description:Doxorubicin is a highly effective cancer treatment whose use is severely limited by dose-dependent cardiotoxicity. It is well established that doxorubicin increases reactive oxygen species (ROS) production. In this study, we investigated contributions to doxorubicin cardiotoxicity from Nox2 NADPH oxidase, an important ROS source in cardiac cells, which is known to modulate several key processes underlying the myocardial response to injury. Nox2-deficient mice (Nox2-/-) and wild-type (WT) controls were injected with doxorubicin (12 mg/kg) or vehicle and studied 8 weeks later. Echocardiography indicated that doxorubicin-induced contractile dysfunction was attenuated in Nox2-/- versus WT mice (fractional shortening: 29.5±1.4 versus 25.7±1.0%; P<0.05). Similarly, in vivo pressure-volume analysis revealed that systolic and diastolic function was preserved in doxorubicin-treated Nox2-/- versus WT mice (ejection fraction: 52.6±2.5 versus 28.5±2.3%, LVdP/dtmin: -8,379±416 versus -5,198±527 mmHg s(-1); end-diastolic pressure-volume relation: 0.051±0.009 versus 0.114±0.012; P<0.001). Furthermore, in response to doxorubicin, Nox2-/- mice exhibited less myocardial atrophy, cardiomyocyte apoptosis, and interstitial fibrosis, together with reduced increases in profibrotic gene expression (procollagen III?I, transforming growth factor-?3, and connective tissue growth factor) and matrix metalloproteinase-9 activity, versus WT controls. These alterations were associated with beneficial changes in NADPH oxidase activity, oxidative/nitrosative stress, and inflammatory cell infiltration. We found that adverse effects of doxorubicin were attenuated by acute or chronic treatment with the AT1 receptor antagonist losartan, which is commonly used to reduce blood pressure. Our findings suggest that ROS specifically derived from Nox2 NADPH oxidase make a substantial contribution to several key processes underlying development of cardiac contractile dysfunction and remodeling associated with doxorubicin chemotherapy.

Dataset Information

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase-induced cardiomyopathy: involvement of mitofusin-2.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Linked articles

Publications

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase-induced cardiomyopathy: involvement of mitofusin-2.

Similar Datasets

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