VCP746, a novel A1 adenosine receptor biased agonist, reduces hypertrophy in a rat neonatal cardiac myocyte model

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Abstract

VCP746 is a novel A1 adenosine receptor (A1AR) biased agonist previously shown to be cytoprotective with no effect on heart rate. The aim of this study was to investigate the potential anti-hypertrophic effect of VCP746 in neonatal rat cardiac myocytes (NCM). NCM hypertrophy was stimulated with interleukin (IL)-1β (10 ng/mL), tumour necrosis factor (TNF)-α (10 ng/mL) or Ang II (100 nmol/L) and was assessed by 3H-leucine incorporation assay. VCP746 significantly inhibited IL-1β-, TNF-α- and Ang II-stimulated NCM hypertrophy as determined by 3H-leucine incorporation. The anti-hypertrophic effect of VCP746 was also more potent than that of the prototypical A1AR agonist, N6-cyclopentyladenosine (CPA). Further investigation with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay showed that neither CPA nor VCP746 had any effect on cell viability, confirming that the reduction in 3H-leucine incorporation mediated by CPA and VCP746 was not due to a reduction in cell viability. IL-1β, TNF-α and Ang II were also shown to increase the mRNA expression of hypertrophy biomarkers, ANP, β-MHC and α-SKA in NCM. Treatment with VCP746 at concentrations as low as 1 nmol/L suppressed mRNA expression of ANP, β-MHC and α-SKA stimulated by IL-1β, TNF-α or Ang II, demonstrating the broad mechanistic basis of the potent anti-hypertrophic effect of VCP746. This study has shown that the novel A1AR agonist, VCP746, is able to attenuate cardiac myocyte hypertrophy. As such, VCP746 is potentially useful as a pharmacological agent in attenuating cardiac remodelling, especially in the post-myocardial infarction setting, given its previously established cytoprotective properties.

Original languageEnglish
Pages (from-to)976-982
Number of pages7
JournalClinical and Experimental Pharmacology and Physiology
Volume43
Issue number10
DOIs
Publication statusPublished - 1 Oct 2016

Keywords

  • adenosine A1-receptor
  • adenosine receptors
  • cardiomyocyte
  • cardiomyocyte hypertrophy
  • cardiovascular pharmacology

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