Periplocymarin Alleviates Doxorubicin-Induced Heart Failure and Excessive Accumulation of Ceramides

Doxorubicin-driven cardiotoxicity could result in dilated cardiomyopathy and heart failure (HF). Previously, we showed that periplocymarin exerted a cardiotonic role by promoting calcium influx and attenuating myocardial fibrosis induced by isoproterenol (ISO) by improving the metabolism of cardiomy...

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Autores principales:	Weijing Yun, Lei Qian, Ruqiang Yuan, Hu Xu
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	periplocymarin doxorubicin heart failure metabolomics ceramide apoptosis Diseases of the circulatory (Cardiovascular) system RC666-701
Acceso en línea:	https://doaj.org/article/91bf8d7834924ee9a355a2e3052e47dc
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spelling	oai:doaj.org-article:91bf8d7834924ee9a355a2e3052e47dc2021-11-19T05:14:27ZPeriplocymarin Alleviates Doxorubicin-Induced Heart Failure and Excessive Accumulation of Ceramides2297-055X10.3389/fcvm.2021.732554https://doaj.org/article/91bf8d7834924ee9a355a2e3052e47dc2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcvm.2021.732554/fullhttps://doaj.org/toc/2297-055XDoxorubicin-driven cardiotoxicity could result in dilated cardiomyopathy and heart failure (HF). Previously, we showed that periplocymarin exerted a cardiotonic role by promoting calcium influx and attenuating myocardial fibrosis induced by isoproterenol (ISO) by improving the metabolism of cardiomyocytes. However, the impact of periplocymarin on doxorubicin (DOX)-triggered cardiomyopathy has not been investigated. In the current study, C57BL/6 mice were randomly divided into three groups, namely, the control, DOX, and DOX+periplocymarin groups. The cardiac function and apoptosis were measured. Our results revealed that periplocymarin administration greatly improved the DOX-induced cardiac dysfunction manifested by the ejection fraction (EF%), fractional shortening (FS%), left ventricular posterior wall thickness (LVPW), left ventricular anterior wall thickness (LVAW), left ventricular (LV) mass, and attenuated DOX-induced cardiomyocyte apoptosis assessed by hematoxylin and eosin (H&E) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and western blotting. Further study using H9c2 cells revealed that the pretreatment of periplocymarin suppressed DOX-induced apoptosis evidenced by annexin V staining. Moreover, liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis demonstrated that DOX lead to an accumulation in serum ceramide, and the pre-treatment of periplocymarin could reverse this phenomenon. Network pharmacology also demonstrated that ceramide metabolism was involved in the process. Consistently, real-time PCR showed that periplocymarin significantly abolished the induction of the genes involved in the de novo synthesis of ceramide, i.e., CerS2, CerS4, CerS5, and CerS6, and the induction was attributed to the treatment of DOX. Collectively, these results suggested that periplocymarin reduced cardiomyocyte apoptosis to protect hearts from DOX-induced cardiotoxicity and the de novo synthesis of ceramides was involved in this process.Weijing YunLei QianRuqiang YuanHu XuFrontiers Media S.A.articleperiplocymarindoxorubicinheart failuremetabolomicsceramideapoptosisDiseases of the circulatory (Cardiovascular) systemRC666-701ENFrontiers in Cardiovascular Medicine, Vol 8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	periplocymarin doxorubicin heart failure metabolomics ceramide apoptosis Diseases of the circulatory (Cardiovascular) system RC666-701
spellingShingle	periplocymarin doxorubicin heart failure metabolomics ceramide apoptosis Diseases of the circulatory (Cardiovascular) system RC666-701 Weijing Yun Lei Qian Ruqiang Yuan Hu Xu Periplocymarin Alleviates Doxorubicin-Induced Heart Failure and Excessive Accumulation of Ceramides
description	Doxorubicin-driven cardiotoxicity could result in dilated cardiomyopathy and heart failure (HF). Previously, we showed that periplocymarin exerted a cardiotonic role by promoting calcium influx and attenuating myocardial fibrosis induced by isoproterenol (ISO) by improving the metabolism of cardiomyocytes. However, the impact of periplocymarin on doxorubicin (DOX)-triggered cardiomyopathy has not been investigated. In the current study, C57BL/6 mice were randomly divided into three groups, namely, the control, DOX, and DOX+periplocymarin groups. The cardiac function and apoptosis were measured. Our results revealed that periplocymarin administration greatly improved the DOX-induced cardiac dysfunction manifested by the ejection fraction (EF%), fractional shortening (FS%), left ventricular posterior wall thickness (LVPW), left ventricular anterior wall thickness (LVAW), left ventricular (LV) mass, and attenuated DOX-induced cardiomyocyte apoptosis assessed by hematoxylin and eosin (H&E) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and western blotting. Further study using H9c2 cells revealed that the pretreatment of periplocymarin suppressed DOX-induced apoptosis evidenced by annexin V staining. Moreover, liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis demonstrated that DOX lead to an accumulation in serum ceramide, and the pre-treatment of periplocymarin could reverse this phenomenon. Network pharmacology also demonstrated that ceramide metabolism was involved in the process. Consistently, real-time PCR showed that periplocymarin significantly abolished the induction of the genes involved in the de novo synthesis of ceramide, i.e., CerS2, CerS4, CerS5, and CerS6, and the induction was attributed to the treatment of DOX. Collectively, these results suggested that periplocymarin reduced cardiomyocyte apoptosis to protect hearts from DOX-induced cardiotoxicity and the de novo synthesis of ceramides was involved in this process.
format	article
author	Weijing Yun Lei Qian Ruqiang Yuan Hu Xu
author_facet	Weijing Yun Lei Qian Ruqiang Yuan Hu Xu
author_sort	Weijing Yun
title	Periplocymarin Alleviates Doxorubicin-Induced Heart Failure and Excessive Accumulation of Ceramides
title_short	Periplocymarin Alleviates Doxorubicin-Induced Heart Failure and Excessive Accumulation of Ceramides
title_full	Periplocymarin Alleviates Doxorubicin-Induced Heart Failure and Excessive Accumulation of Ceramides
title_fullStr	Periplocymarin Alleviates Doxorubicin-Induced Heart Failure and Excessive Accumulation of Ceramides
title_full_unstemmed	Periplocymarin Alleviates Doxorubicin-Induced Heart Failure and Excessive Accumulation of Ceramides
title_sort	periplocymarin alleviates doxorubicin-induced heart failure and excessive accumulation of ceramides
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/91bf8d7834924ee9a355a2e3052e47dc
work_keys_str_mv	AT weijingyun periplocymarinalleviatesdoxorubicininducedheartfailureandexcessiveaccumulationofceramides AT leiqian periplocymarinalleviatesdoxorubicininducedheartfailureandexcessiveaccumulationofceramides AT ruqiangyuan periplocymarinalleviatesdoxorubicininducedheartfailureandexcessiveaccumulationofceramides AT huxu periplocymarinalleviatesdoxorubicininducedheartfailureandexcessiveaccumulationofceramides
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Periplocymarin Alleviates Doxorubicin-Induced Heart Failure and Excessive Accumulation of Ceramides

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