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PI3Kα Pathway Inhibition With Doxorubicin Treatment Results in Distinct Biventricular Atrophy and Remodeling With Right Ventricular Dysfunction

McLean, BA; Patel, VB; Zhabyeyev, P; Chen, X; Basu, R; Wang, F; Shah, S; ... Oudit, GY; + view all (2019) PI3Kα Pathway Inhibition With Doxorubicin Treatment Results in Distinct Biventricular Atrophy and Remodeling With Right Ventricular Dysfunction. Journal of the American Heart Association , 8 (9) , Article e010961. 10.1161/JAHA.118.010961. Green open access

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Abstract

Background-—Cancer therapies inhibiting PI3Ka (phosphoinositide 3-kinase-a)–dependent growth factor signaling, including trastuzumab inhibition of HER2 (Human Epidermal Growth Factor Receptor 2), can cause adverse effects on the heart. Direct inhibition of PI3Ka is now in clinical trials, but the effects of PI3Ka pathway inhibition on heart atrophy, remodeling, and function in the context of cancer therapy are not well understood. Method and Results-—Pharmacological PI3Ka inhibition and heart-specific genetic deletion of p110a, the catalytic subunit of PI3Ka, was characterized in conjunction with anthracycline (doxorubicin) treatment in female murine models. Biventricular changes in heart morphological characteristics and function were analyzed, with molecular characterization of signaling pathways. Both PI3Ka inhibition and anthracycline therapy promoted heart atrophy and a combined effect of distinct right ventricular dilation, dysfunction, and cardiomyocyte remodeling in the absence of pulmonary arterial hypertension. Congruent findings of right ventricular dilation and dysfunction were seen with pharmacological and genetic suppression of PI3Ka signaling when combined with doxorubicin treatment. Increased p38 mitogen-activated protein kinase activation was mechanistically linked to heart atrophy and correlated with right ventricular dysfunction in explanted failing human hearts. Conclusions-—PI3Ka pathway inhibition promotes heart atrophy in mice. The right ventricle is specifically at risk for dilation and dysfunction in the setting of PI3K inhibition in conjunction with chemotherapy. Inhibition of p38 mitogen-activated protein kinase is a proposed therapeutic target to minimize this mode of cardiotoxicity

Type: Article
Title: PI3Kα Pathway Inhibition With Doxorubicin Treatment Results in Distinct Biventricular Atrophy and Remodeling With Right Ventricular Dysfunction
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1161/JAHA.118.010961
Publisher version: https://doi.org/10.1161/JAHA.118.010961
Language: English
Additional information: This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. https://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords: anthracycline • heart atrophy • PI3K • remodeling • right ventricle
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10074143
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