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Cytochrome c oxidase is essential for copper-induced regression of cardiomyocyte hypertrophy
Xiao Zuo1, Huiqi Xie, Daoyin Dong
1Regenerative Medicine Research Center and Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
Insights
Copper and vascular endothelial growth factor (VEGF) reduce cardiomyocyte hypertrophy by restoring cytochrome c oxidase (COX) activity. This study confirms COX is crucial for both copper and VEGF-mediated regression of enlarged heart cells.
Area of Science:
- Cardiovascular Biology
- Cellular Physiology
Background:
- Hypertrophic cardiomyopathy is linked to reduced cytochrome c oxidase (COX) activity.
- Copper (Cu) and vascular endothelial growth factor (VEGF) are known to reduce cardiomyocyte size, with Cu's effect being VEGF-dependent.
Purpose of the Study:
- To investigate the role of COX as a key factor in copper-induced regression of cardiomyocyte hypertrophy.
- To determine if COX activity mediates the effects of both copper and VEGF on hypertrophic cardiomyocytes.
Main Methods:
- Induction of cardiomyocyte hypertrophy using phenylephrine (PE) in primary neonatal rat cardiomyocyte cultures.
- Treatment with copper sulfate and/or VEGF, with and without COX inhibition via gene silencing (siRNA targeting COX-I).
- Assessment of cell size, protein content, molecular markers, and COX activity.
Main Results:
- PE-induced hypertrophy decreased COX activity; copper addition restored COX activity and reversed hypertrophy.
- Gene silencing of COX-I inhibited COX activity and blocked copper-induced regression.
- VEGF restored COX activity and induced regression, but this effect was blocked by COX inhibition.
Conclusions:
- Cytochrome c oxidase (COX) activity is depressed in hypertrophic cardiomyocytes.
- Both copper and VEGF restore COX activity, playing a determinant role in the regression of cardiomyocyte hypertrophy.
- COX is a critical mediator for both copper- and VEGF-induced beneficial effects on hypertrophic heart cells.
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 100 microM in cultures for 48 h to induce cell hypertrophy. The hypertrophic cells were then treated with Cu sulfate at a final concentration of 5 microM 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.
