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Cytochrome c Oxidase is Essential for Copper-Induced Regression of Cardiomyocyte Hypertrophy

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Abstract

Previous studies have shown that both copper (Cu) and vascular endothelial growth factor (VEGF) reduce the size of hypertrophic cardiomyocytes, but the Cu-induced regression is VEGF dependent. Studies in vivo have shown that hypertrophic cardiomyopathy is associated with a depression in cytochrome c oxidase (COX) activity, which could be involved in VEGF-mediated cellular function. The present study was undertaken to test the hypothesis that COX is a determinant factor in Cu-induced regression of cardiomyocyte hypertrophy. Primary cultures of neonatal rat cardiomyocytes were treated with phenylepherine (PE) at a final concentration of l00 μM in cultures for 48 h to induce cell hypertrophy. The hypertrophic cells were then treated with Cu sulfate at a final concentration of 5 μM in cultures for 24 h with a concomitant presence of PE to examine the effect of Cu on the regression of cardiomyocyte hypertrophy. Cell size changes were determined by flow cytometry, protein content, and molecular markers. Gene silencing was applied to study the effect of COX activity change on the regression of cardiomyocyte hypertrophy. PE treatment decreased COX activity in hypertrophic cardiomyocytes, and Cu addition restored the activity along with the regression of cell hypertrophy. Gene silencing using siRNA targeting COX-I significantly inhibited COX activity and blocked the Cu-induced regression of cell hypertrophy. VEGF alone also restored COX activity; but under the condition of COX inhibition by gene silencing, VEGF-induced regression of cell hypertrophy was suppressed. This study demonstrates that both Cu and VEGF can restore COX activity that is depressed in hypertrophic cardiomyocytes, and COX plays a determinant role in both Cu- and VEGF-induced regression of cardiomyocyte hypertrophy.

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Acknowledgments

The authors thank Xiaohe Chen and Shengfu Li for technical support. This work was supported in part by West China Hospital and Sichuan University and by US National Institutes of Health [HL63760 to YJK].

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Authors and Affiliations

  1. Regenerative Medicine Research Center and Laboratory of Stem Cell and Tissue Engineering of the State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China

    Xiao Zuo, Huiqi Xie, Daoyin Dong, Hongming Zhu & Y. James Kang

  2. Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China

    Nenggang Jiang

  3. Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40202, USA

    Y. James Kang

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  1. Xiao Zuo
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  2. Huiqi Xie
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  4. Nenggang Jiang
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  5. Hongming Zhu
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Correspondence to Y. James Kang.

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Xiao Zuo and Huiqi Xie made equal contributions to this study.

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Zuo, X., Xie, H., Dong, D. et al. Cytochrome c Oxidase is Essential for Copper-Induced Regression of Cardiomyocyte Hypertrophy. Cardiovasc Toxicol 10, 208–215 (2010). https://doi.org/10.1007/s12012-010-9080-0

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