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Int J Biol Sci 2019; 15(3):556-567. doi:10.7150/ijbs.29907

Research Paper

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

Xin Zhang*, Jin-Xiu Zhu*, Zhen-Guo Ma, Hai-Ming Wu, Si-Chi Xu, Peng Song, Chun-Yan Kong, Yu-Pei Yuan, Wei Deng, Qi-Zhu Tang

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, RP China
Cardiovascular Research Institute of Wuhan University, Wuhan 430060, RP China
Hubei Key Laboratory of Cardiology, Wuhan 430060, RP China
* These authors contributed equally to this work.

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.

Keywords: Rosmarinic acid, Apoptosis, Cardiac fibroblast, Fas ligand, Nuclear factor of activated T cells, Metalloproteinase.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Zhang X, Zhu JX, Ma ZG, Wu HM, Xu SC, Song P, Kong CY, Yuan YP, Deng W, Tang QZ. Rosmarinic acid alleviates cardiomyocyte apoptosis via cardiac fibroblast in doxorubicin-induced cardiotoxicity. Int J Biol Sci 2019; 15(3):556-567. doi:10.7150/ijbs.29907. Available from http://www.ijbs.com/v15p0556.htm