细胞色素 c 氧化酶对于铜诱导的心肌细胞肥大消退是必需的。
Cytochrome c oxidase is essential for copper-induced regression of cardiomyocyte hypertrophy.
机构信息
Regenerative 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.
出版信息
Cardiovasc Toxicol. 2010 Sep;10(3):208-15. doi: 10.1007/s12012-010-9080-0.
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.
先前的研究表明，铜（Cu）和血管内皮生长因子（VEGF）均可减小心肌细胞的肥大程度，但 Cu 诱导的心肌细胞肥大回缩依赖于 VEGF。体内研究表明，肥厚型心肌病与细胞色素 c 氧化酶（COX）活性降低有关，而 COX 活性降低可能与 VEGF 介导的细胞功能有关。本研究旨在验证 COX 是否为 Cu 诱导的心肌细胞肥大回缩的决定因素。将新生大鼠心肌细胞原代培养物用终浓度为 100 μM 的苯肾上腺素（PE）处理 48 h 以诱导细胞肥大。然后将肥大细胞用终浓度为 5 μM 的 CuSO4 在含有 PE 的培养基中处理 24 h，以观察 Cu 对心肌细胞肥大回缩的影响。通过流式细胞术、蛋白含量和分子标志物来确定细胞大小的变化。基因沉默用于研究 COX 活性变化对心肌细胞肥大回缩的影响。PE 处理降低了肥大心肌细胞中的 COX 活性，而 Cu 添加则恢复了活性，同时也使细胞肥大回缩。使用靶向 COX-I 的 siRNA 进行基因沉默显著抑制了 COX 活性，并阻断了 Cu 诱导的细胞肥大回缩。VEGF 本身也能恢复 COX 活性；但在 COX 被基因沉默抑制的情况下，VEGF 诱导的细胞肥大回缩受到抑制。本研究表明，Cu 和 VEGF 均可恢复肥厚心肌细胞中活性降低的 COX，而 COX 在 Cu 和 VEGF 诱导的心肌细胞肥大回缩中起决定作用。
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