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Int J Biol Sci. 2019 Jan 1;15(3):556-567. doi: 10.7150/ijbs.29907. eCollection 2019.

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

Zhang X1,2,3, Zhu JX1,2,3, Ma ZG1,2,3, Wu HM1,2,3, Xu SC1,2,3, Song P1,2,3, Kong CY1,2,3, Yuan YP1,2,3, Deng W1,2,3, Tang QZ1,2,3.

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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.


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.


Apoptosis; Cardiac fibroblast; Fas ligand; Metalloproteinase.; Nuclear factor of activated T cells; Rosmarinic acid

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

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