Copper-induced regression of cardiomyocyte hypertrophy is associated with enhanced vascular endothelial growth factor receptor-1 signalling pathway

Yang Zhou, Katherine Bourcy, Yujian Kang

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

AimsVascular 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 resultsPrimary cultures of neonatal rat cardiomyocytes were exposed to phenylephrine (PE) at a final concentration of 100 M in cultures for 48 h to induce cell hypertrophy. The hypertrophic cardiomyocytes were exposed to copper sulfate at a final concentration of 5 M 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. ConclusionEnhanced VEGFR-1 signalling is involved in Cu regression of cardiomyocyte hypertrophy, and the PKG-1 pathway is likely associated with VEGFR-1.

Original languageEnglish (US)
Pages (from-to)54-63
Number of pages10
JournalCardiovascular Research
Volume84
Issue number1
DOIs
StatePublished - Oct 1 2009
Externally publishedYes

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Vascular Endothelial Growth Factor Receptor-1
Vascular Endothelial Growth Factor Receptor
Cardiac Myocytes
Hypertrophy
Copper
Gene Silencing
Vascular Endothelial Growth Factor A
Phenylephrine
Endothelial Growth Factors
Copper Sulfate
Cyclic GMP-Dependent Protein Kinases
Cardiomegaly
Culture Media
Cell Differentiation
Anti-Idiotypic Antibodies
Flow Cytometry
Enzyme-Linked Immunosorbent Assay
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Copper-induced regression of cardiomyocyte hypertrophy is associated with enhanced vascular endothelial growth factor receptor-1 signalling pathway. / Zhou, Yang; Bourcy, Katherine; Kang, Yujian.

In: Cardiovascular Research, Vol. 84, No. 1, 01.10.2009, p. 54-63.

Research output: Contribution to journalArticle

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N2 - AimsVascular 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 resultsPrimary cultures of neonatal rat cardiomyocytes were exposed to phenylephrine (PE) at a final concentration of 100 M in cultures for 48 h to induce cell hypertrophy. The hypertrophic cardiomyocytes were exposed to copper sulfate at a final concentration of 5 M 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. ConclusionEnhanced VEGFR-1 signalling is involved in Cu regression of cardiomyocyte hypertrophy, and the PKG-1 pathway is likely associated with VEGFR-1.

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