Copper-induced regression of cardiomyocyte hypertrophy is associated with enhanced vascular endothelial growth factor receptor-1 signalling pathway.
Copper-induced regression of cardiomyocyte hypertrophy is associated with enhanced vascular endothelial growth factor receptor-1 signalling pathway.
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DOI：
10.1093/cvr/cvp178
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发表时间：
2009-10
影响因子：
10.8
通讯作者：
Yang Zhou;Katherine Bourcy;Y. J. Kang
中科院分区：
文献类型：
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作者：
Yang Zhou;Katherine Bourcy;Y. J. Kang
目的血管内皮生长因子(VEGF)具有刺激细胞增殖和分化的作用，但我们观察到铜(Cu)诱导的心肌肥厚消退是依赖于血管内皮生长因子的。本研究旨在验证铜引起肥大心肌细胞血管内皮生长因子受体(VEGFRs)分布改变的假说，从而将信号通路从刺激细胞生长切换到逆转细胞肥大。方法与结果用终浓度为100微米的苯肾上腺素(PE)诱导原代培养乳鼠心肌细胞肥大48h。将肥大的心肌细胞暴露于终浓度为5微米的硫酸铜中培养24小时，同时加入PE。采用流式细胞术、基因沉默和ELISA法分析血管内皮生长因子受体的变化及其与心肌细胞肥大消退的关系。铜不改变培养上清液中血管内皮生长因子的浓度，但使VEGFR-1/VEGFR-2的比例增加一倍。在无铜添加的情况下，VEGFR-2基因沉默可逆转PE诱导的心肌细胞肥大，这种肥大可被抗血管内皮生长因子抗体抑制。VEGFR-1基因沉默可阻断铜诱导的细胞肥大消退，并降低cGMP依赖的蛋白激酶-1(PKG-1)活性。PKG-1拮抗剂RP-8-PCPT-cGMPS可阻断铜和VEGFR-2基因沉默诱导的心肌肥厚消退。结论VEGFR-1信号增强参与了心肌肥厚的铜消退过程，PKG-1信号通路可能与VEGFR-1有关。
AIMS Vascular endothelial growth factor (VEGF) has been well documented to stimulate cell proliferation and differentiation; however, we have observed that copper (Cu)-induced regression of heart hypertrophy was VEGF-dependent. The present study was undertaken to test the hypothesis that Cu causes alterations in the distribution of VEGF receptors (VEGFRs) in hypertrophic cardiomyocytes so that it switches the signalling pathway from stimulation of cell growth to reversal of cell hypertrophy. METHODS AND RESULTS Primary cultures of neonatal rat cardiomyocytes were exposed to phenylephrine (PE) at a final concentration of 100 microM in cultures for 48 h to induce cell hypertrophy. The hypertrophic cardiomyocytes were exposed to copper sulfate at a final concentration of 5 microM in cultures for 24 h with a concomitant presence of PE. Flow cytometry, gene silencing, and ELISA procedures were used to analyse the changes in VEGFRs and their relationship with regression of cardiomyocyte hypertrophy. Cu did not change the concentration of VEGF in culture media, but increased the ratio of VEGFR-1 to VEGFR-2 two-fold. Gene silencing of VEGFR-2, in the absence of Cu addition, reversed PE-induced cardiomyocyte hypertrophy, which was suppressed by an anti-VEGF antibody. Gene silencing of VEGFR-1 blocked Cu-induced regression of cell hypertrophy and decreased the activity of cGMP-dependent protein kinase-1 (PKG-1). A PKG-1 antagonist, Rp-8-pCPT-cGMPS, blocked both Cu- and VEGFR-2 gene silencing-induced regression of cardiomyocyte hypertrophy. CONCLUSION Enhanced VEGFR-1 signalling is involved in Cu regression of cardiomyocyte hypertrophy, and the PKG-1 pathway is likely associated with VEGFR-1.