title: Vascular endothelial growth factor recovers suppressed cytochrome c oxidase activity by restoring copper availability in hypertrophic cardiomyocytes.
abstract: Cardiomyocyte hypertrophy induced by phenylepherine (PE) is accompanied by depression of cytochrome c oxidase (COX) activity. Vascular endothelial growth factor (VEGF) recovers the suppressed COX activity and reverses cardiomyocyte hypertrophy. Because PE causes intracellular copper (Cu) depletion and COX activity is Cu-dependent, the present study was undertaken to test the hypothesis that VEGF recovers suppressed COX activity by restoring Cu availability. Primary cultures of neonatal rat cardiomyocytes were treated with PE at a final concentration of 100 µmol/L in cultures for 48 h to induce cell hypertrophy. The hypertrophic cardiomyocytes were exposed to VEGF at a final concentration of 20 ng/mL in cultures for 24 h. Atomic absorption spectrometry analysis revealed that VEGF restored PE-depleted Cu concentrations in hypertrophic cardiomyocytes along with the recovery of COX activity. Western blot analysis showed that protein contents of COX subunit COX-IV and Cu chaperones for COX (COX17, COX11, and SCO2) were decreased in response to PE treatment, and recovered after VEGF treatment. In addition, VEGF treatment suppressed PE-induced accumulation of reactive oxygen species (ROS) and the relevant elevation of homocysteine, which has been shown to form complexes with Cu to restrict Cu availability. This study thus demonstrates that VEGF recovers PE-suppressed COX activity by restoring Cu availability and VEGF suppression of ROS accumulation and homocysteine elevation would contribute to the increased Cu availability.
authors.affiliation: Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China.
authors.forename: Miao
authors.initials: M
authors.lastname: Sun
authors.affiliation: Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zuo
authors.affiliation: Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China yjkang01@louisville.edu.
authors.forename: Y James
authors.initials: YJ
authors.lastname: Kang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003300:Copper / Q000378:metabolism*; D003600:Cytosol / Q000737:chemistry; D003576:Electron Transport Complex IV / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology*; D017207:Rats, Sprague-Dawley; D013054:Spectrophotometry, Atomic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D003300:Copper; D003576:Electron Transport Complex IV
keywords: Cardiomyocyte; cytochrome c oxidase; homocysteine; hypertrophy; vascular endothelial growth factor