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Vascular endothelial growth factor recovers suppressed cytochrome c oxidase activity by restoring copper availability
1Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China.
Insights
Vascular endothelial growth factor (VEGF) restores copper levels and cytochrome c oxidase (COX) activity suppressed by phenylephrine (PE). VEGF also reduces reactive oxygen species and homocysteine, aiding copper availability in cardiomyocytes.
Area of Science:
- Biochemistry
- Cell Biology
- Cardiovascular Research
Background:
- Phenylephrine (PE) induces cardiomyocyte hypertrophy, suppressing cytochrome c oxidase (COX) activity.
- This suppression is linked to intracellular copper (Cu) depletion, as COX activity is Cu-dependent.
- Vascular endothelial growth factor (VEGF) is known to reverse PE-induced cardiomyocyte hypertrophy and COX suppression.
Purpose of the Study:
- To investigate if VEGF restores suppressed COX activity by increasing copper availability.
- To elucidate the role of copper in VEGF's protective effects against PE-induced cardiomyocyte hypertrophy.
Main Methods:
- Neonatal rat cardiomyocytes were treated with PE to induce hypertrophy, followed by VEGF treatment.
- Copper concentrations were measured using atomic absorption spectrometry.
- COX activity, COX subunit protein levels, copper chaperone expression, reactive oxygen species (ROS), and homocysteine levels were analyzed via Western blot and other assays.
Main Results:
- VEGF treatment restored PE-suppressed copper concentrations in hypertrophic cardiomyocytes.
- VEGF recovered COX activity and normalized the protein levels of COX-IV and copper chaperones (COX17, COX11, SCO2).
- VEGF suppressed PE-induced ROS accumulation and homocysteine elevation, which interfere with copper availability.
Conclusions:
- VEGF restores phenylephrine-suppressed COX activity by increasing intracellular copper availability.
- VEGF's beneficial effects are mediated, in part, by restoring copper homeostasis.
- VEGF's suppression of ROS and homocysteine contributes to enhanced copper availability in 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.
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