Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway

Context: Sunitinib (SU) is a multi-targeted tyrosine kinase inhibitor anticancer agent whose clinical use is often limited by cardiovascular complications. Trimetazidine (TMZ) is an anti-angina agent that has been demonstrated cardioprotective effects in numerous cardiovascular conditions, but its p...

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Autores principales:	Yi Yang, Na Li, Tongshuai Chen, Chunmei Zhang, Lingxin Liu, Yan Qi, Peili Bu
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2019
Materias:	hypertension left ventricular dysfunction cardiomyocyte tyrosine kinase inhibitor Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/5ad1ba90404b445aadedc190f4a54bdf
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spelling	oai:doaj.org-article:5ad1ba90404b445aadedc190f4a54bdf2021-11-17T14:21:56ZTrimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway1388-02091744-511610.1080/13880209.2019.1657905https://doaj.org/article/5ad1ba90404b445aadedc190f4a54bdf2019-01-01T00:00:00Zhttp://dx.doi.org/10.1080/13880209.2019.1657905https://doaj.org/toc/1388-0209https://doaj.org/toc/1744-5116Context: Sunitinib (SU) is a multi-targeted tyrosine kinase inhibitor anticancer agent whose clinical use is often limited by cardiovascular complications. Trimetazidine (TMZ) is an anti-angina agent that has been demonstrated cardioprotective effects in numerous cardiovascular conditions, but its potential effects in SU-induced cardiotoxicity have not been investigated. Objective: This study investigates the effect of TMZ in sunitinib-induced cardiotoxicity in vivo and in vitro and molecular mechanisms. Materials and methods: Male 129S1/SvImJ mice were treated with vehicle, SU (40 mg/kg/d) or SU and TMZ (20 mg/kg/d) via oral gavage for 28 days, and cardiovascular functions and cardiac protein expressions were examined. H9c2 cardiomyocytes were treated with vehicle, SU (2–10 μM) or SU and TMZ (40–120 μM) for 48 h, and cell viability, apoptosis, autophagy, and protein expression was tested. Results: SU induces hypertension (systolic blood pressure [SBP] + 28.33 ± 5.00 mmHg) and left ventricular dysfunction (left ventricular ejection fraction [LVEF] − 11.16 ± 2.53%) in mice. In H9c2 cardiomyocytes, SU reduces cell viability (IC50 4.07 μM) and inhibits the AMPK/mTOR/autophagy pathway (p < 0.05). TMZ co-administration with SU reverses SU-induced cardiotoxicity in mice (SBP − 23.75 ± 4.69 mmHg, LVEF + 10.95 ± 3.317%), alleviates cell viability loss in H9c2 cardiomyocytes (p < 0.01) and activates the AMPK/mTOR/autophagy pathway in vivo (p < 0.001) and in vitro (p < 0.05). Discussion and conclusions: Our results suggest TMZ as a potential cardioprotective approach for cardiovascular complications during SU regimen, and potentially for cardiotoxicity of other anticancer chemotherapies associated with cardiomyocyte autophagic pathways.Yi YangNa LiTongshuai ChenChunmei ZhangLingxin LiuYan QiPeili BuTaylor & Francis Grouparticlehypertensionleft ventricular dysfunctioncardiomyocytetyrosine kinase inhibitorTherapeutics. PharmacologyRM1-950ENPharmaceutical Biology, Vol 57, Iss 1, Pp 625-631 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	hypertension left ventricular dysfunction cardiomyocyte tyrosine kinase inhibitor Therapeutics. Pharmacology RM1-950
spellingShingle	hypertension left ventricular dysfunction cardiomyocyte tyrosine kinase inhibitor Therapeutics. Pharmacology RM1-950 Yi Yang Na Li Tongshuai Chen Chunmei Zhang Lingxin Liu Yan Qi Peili Bu Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway
description	Context: Sunitinib (SU) is a multi-targeted tyrosine kinase inhibitor anticancer agent whose clinical use is often limited by cardiovascular complications. Trimetazidine (TMZ) is an anti-angina agent that has been demonstrated cardioprotective effects in numerous cardiovascular conditions, but its potential effects in SU-induced cardiotoxicity have not been investigated. Objective: This study investigates the effect of TMZ in sunitinib-induced cardiotoxicity in vivo and in vitro and molecular mechanisms. Materials and methods: Male 129S1/SvImJ mice were treated with vehicle, SU (40 mg/kg/d) or SU and TMZ (20 mg/kg/d) via oral gavage for 28 days, and cardiovascular functions and cardiac protein expressions were examined. H9c2 cardiomyocytes were treated with vehicle, SU (2–10 μM) or SU and TMZ (40–120 μM) for 48 h, and cell viability, apoptosis, autophagy, and protein expression was tested. Results: SU induces hypertension (systolic blood pressure [SBP] + 28.33 ± 5.00 mmHg) and left ventricular dysfunction (left ventricular ejection fraction [LVEF] − 11.16 ± 2.53%) in mice. In H9c2 cardiomyocytes, SU reduces cell viability (IC50 4.07 μM) and inhibits the AMPK/mTOR/autophagy pathway (p < 0.05). TMZ co-administration with SU reverses SU-induced cardiotoxicity in mice (SBP − 23.75 ± 4.69 mmHg, LVEF + 10.95 ± 3.317%), alleviates cell viability loss in H9c2 cardiomyocytes (p < 0.01) and activates the AMPK/mTOR/autophagy pathway in vivo (p < 0.001) and in vitro (p < 0.05). Discussion and conclusions: Our results suggest TMZ as a potential cardioprotective approach for cardiovascular complications during SU regimen, and potentially for cardiotoxicity of other anticancer chemotherapies associated with cardiomyocyte autophagic pathways.
format	article
author	Yi Yang Na Li Tongshuai Chen Chunmei Zhang Lingxin Liu Yan Qi Peili Bu
author_facet	Yi Yang Na Li Tongshuai Chen Chunmei Zhang Lingxin Liu Yan Qi Peili Bu
author_sort	Yi Yang
title	Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway
title_short	Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway
title_full	Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway
title_fullStr	Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway
title_full_unstemmed	Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway
title_sort	trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the ampk/mtor/autophagy pathway
publisher	Taylor & Francis Group
publishDate	2019
url	https://doaj.org/article/5ad1ba90404b445aadedc190f4a54bdf
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Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway

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