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Fosinopril Attenuates the Doxorubicin-induced Cardiomyopathy by Restoring the Function of Sarcoplasmic Reticulum

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Abstract

Fosinopril, an angiotensin-converting enzyme inhibitor, is known to attenuate cardiomyopathy induced by doxorubicin (DOX); however, the mechanisms of this cardioprotection are not fully elucidated yet. In the present study, experimental cardiomyopathy was induced in rats by administration of DOX with or without co-treatment with fosinopril. Fosinopril was utilized on day 1 or 14 of the treatment with DOX to compare efficacies of early versus late co-treatments. We observed that fosinopril attenuated changes induced by DOX (e.g., less increased heart and left ventricular weights, diminished lung congestion and ascites, attenuated LVEDP and LVSP, and less decreased +dP/dt and −dP/dt). Further, fosinopril diminished the levels of markers of cardiac toxicity (i.e., plasma levels and activities of cardiac enzymes and proteins AST, LDH, CPK, cTnI, and BNP). Fosinopril also prevented DOX-induced decreases in Ca2+ uptake and restored activity of Ca2+-stimulated ATPase in left ventricular sarcoplasmic reticulum. We next tested whether the improved Ca2+ transport activity in sarcoplasmic reticulum was due to modulation of SERCA2 and phospholamban expressions by fosinopril. Fosinopril attenuated the decrease in SERCA2 and phospholamban expressions caused by DOX. In conclusion, cardioprotective effects of fosinopril in the DOX-induced cardiomyopathy appear to be due to its ability to prevent remodeling of the cardiac sarcoplasmic reticulum membrane.

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Acknowledgments

The authors gratefully acknowledge continuing support from the Natural Science Foundation of Shanghai Municipal Scientific Committee.

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Authors and Affiliations

  1. Division of Cardiology, Xinhua Hospital School of Medicine, Shanghai Jiaotong University, 1665 Kong Jiang Road, Shanghai, 200092, China

    Ya-chen Zhang, Yong Tang, Min Zhang, Jian Chen, Qing Zhou, Ying-gang Sun, Man-tian Chen & Wei-ping Xu

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  1. Ya-chen Zhang
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  2. Yong Tang
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  3. Min Zhang
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  5. Qing Zhou
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  7. Man-tian Chen
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Correspondence to Man-tian Chen or Wei-ping Xu.

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Ya-chen Zhang and Yong Tang have contributed equally to the study.

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Zhang, Yc., Tang, Y., Zhang, M. et al. Fosinopril Attenuates the Doxorubicin-induced Cardiomyopathy by Restoring the Function of Sarcoplasmic Reticulum. Cell Biochem Biophys 64, 205–211 (2012). https://doi.org/10.1007/s12013-012-9386-6

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