Cardiovascular Research Advance Access originally published online on June 19, 2009
Cardiovascular Research 2009 84(1):54-63; doi:10.1093/cvr/cvp178
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Copper-induced regression of cardiomyocyte hypertrophy is associated with enhanced vascular endothelial growth factor receptor-1 signalling pathway
1 Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA
2 Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
* Corresponding author. Tel: +1 502 852 8677; fax: +1 502 852 6904. E-mail address: yjkang01{at}louisville.edu
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 µM in cultures for 48 h to induce cell hypertrophy. The hypertrophic cardiomyocytes were exposed to copper sulfate at a final concentration of 5 µM 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.
KEYWORDS VEGF; VEGFR; PKG-1; Copper; Cardiomyocyte; Hypertrophy
Time for primary review: 25 days
Related Article
CiteULike 
Connotea 
Del.icio.us What's this?
Cardiovasc Res 2009 84: 4-6.
This article has been cited by other articles:
|
|
 |
|
  R. Madonna and R. De Caterina VEGF receptor switching in heart development and disease Cardiovasc Res, October 1, 2009; 84(1): 4 - 6. [Full Text] [PDF]
|
|