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Rosmarinic acid alleviates cardiomyocyte apoptosis via cardiac fibroblast in doxorubicin-induced cardiotoxicity.

ABSTRACT: Cardiomyocyte apoptosis is a key event in the process of doxorubicin (DOX)-induced cardiotoxicity. Our previous study found that rosmarinic acid (RA) could attenuate pressure overload-induced cardiac dysfunction via cardiac fibroblasts (CFs), however its effect in DOX-induced cardiotoxicity remains unknown. In the present study, mice were subjected to a single intraperitoneal injection of DOX (15mg/kg) to generate DOX-induced cardiotoxicity. Histological examination, echocardiography, and molecular markers were used to evaluate the effects of RA. Neonatal rat cardiomyocytes (CMs) and CFs were used to verify the protective effect of RA in vitro. Conditioned medium derived from RA-treated CFs were prepared to illustrate the effect of RA on paracrine interplay between CFs and CMs. We found that RA significantly alleviated DOX-induced cardiomyocyte apoptosis and cardiac dysfunction in vivo, which, however, had almost negligible beneficial effect on DOX directly induced cardiomyocyte apoptosis in vitro. Mechanistically, CFs-derived Fas L was responsible for DOX-induced cardiomyocyte apoptosis, and RA treatment could decrease Fas L expression in CFs and its release to the conditioned medium by suppressing nuclear factor of activated T cells (NFAT) activation and metalloproteinase 7 (MMP7) expression, and exerted the anti-apoptotic effect on CMs via CFs. Ionomycin, and activator of NFAT, abrogated RA-mediated protective effect on cardiomyocyte apoptosis and cardiac dysfunction. In summary, RA alleviated cardiomyocyte apoptosis by inhibiting the expression and release of Fas L in CFs via a paracrine manner, moreover, NFAT as well as MMP7 inhibition were responsible for the suppression of Fas L. RA could be a powerful new therapeutic agent to mitigate cardiomyocyte apoptosis, thereby improving DOX-induced cardiotoxicity.

SUBMITTER: Zhang X

PROVIDER: S-EPMC6367577 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Rosmarinic acid alleviates cardiomyocyte apoptosis via cardiac fibroblast in doxorubicin-induced cardiotoxicity.

Zhang Xin X Zhu Jin-Xiu JX Ma Zhen-Guo ZG Wu Hai-Ming HM Xu Si-Chi SC Song Peng P Kong Chun-Yan CY Yuan Yu-Pei YP Deng Wei W Tang Qi-Zhu QZ

International journal of biological sciences 20190101 3

Cardiomyocyte apoptosis is a key event in the process of doxorubicin (DOX)-induced cardiotoxicity. Our previous study found that rosmarinic acid (RA) could attenuate pressure overload-induced cardiac dysfunction via cardiac fibroblasts (CFs), however its effect in DOX-induced cardiotoxicity remains unknown. In the present study, mice were subjected to a single intraperitoneal injection of DOX (15mg/kg) to generate DOX-induced cardiotoxicity. Histological examination, echocardiography, and molecu ...[more]

PMID: 30745842

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Project description:BackgroundInflammation, oxidative stress, and apoptosis contribute to the evolution of doxorubicin (DOX)-induced cardiotoxicity. Osteocrin (OSTN) is a novel secretory peptide mainly derived from the bone and skeletal muscle, and plays critical roles in regulating bone growth and physical endurance. Inspiringly, OSTN was also reported to be abundant in the myocardium that functioned as a therapeutic agent against cardiac rupture and congestive heart failure in mice after myocardial infarction. Herein, we investigated the role and potential mechanism of OSTN in DOX-induced cardiotoxicity.MethodsCardiac-restrict OSTN overexpression was performed by the intravenous injection of a cardiotropic AAV9 vector, and subsequently the mice received 15 mg/kg DOX injection (i.p., once) to induce acute cardiac injury. Besides, H9C2 cell lines were used to assess the possible role of OSTN in vitro by incubating with recombinant human OSTN or small interfering RNA against Ostn (siOstn). To clarify the involvement of protein kinase G (PKG), KT5823 and siPkg were used in vivo and in vitro. Mice were also administrated intraperitoneally with 5 mg/kg DOX weekly for consecutive 3 weeks at a cumulative dose of 15 mg/kg to mimic the cardiotoxic effects upon chronic DOX exposure.ResultsOSTN treatment notably attenuated, whereas OSTN silence exacerbated inflammation, oxidative stress, and cardiomyocyte apoptosis in DOX-treated H9C2 cells. Besides, cardiac-restrict OSTN-overexpressed mice showed an alleviated cardiac injury and malfunction upon DOX injection. Mechanistically, we found that OSTN activated PKG, while PKG inhibition abrogated the beneficial effect of OSTN in vivo and in vitro. As expected, OSTN overexpression also improved cardiac function and survival rate in mice after chronic DOX treatment.ConclusionsOSTN protects against DOX-elicited inflammation, oxidative stress, apoptosis, and cardiac dysfunction via activating PKG, and cardiac gene therapy with OSTN provides a novel therapeutic strategy against DOX-induced cardiotoxicity.

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Rosmarinic acid alleviates cardiomyocyte apoptosis via cardiac fibroblast in doxorubicin-induced cardiotoxicity.

Publications

Rosmarinic acid alleviates cardiomyocyte apoptosis via cardiac fibroblast in doxorubicin-induced cardiotoxicity.

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