Projects per year
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 language | English |
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Pages (from-to) | 976-982 |
Number of pages | 7 |
Journal | Clinical and Experimental Pharmacology and Physiology |
Volume | 43 |
Issue number | 10 |
DOIs | |
Publication status | Published - 1 Oct 2016 |
Keywords
- adenosine A1-receptor
- adenosine receptors
- cardiomyocyte
- cardiomyocyte hypertrophy
- cardiovascular pharmacology
Projects
- 3 Finished
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Adenosine Receptor Biased Agonism to Treat Ischaemic Heart Disease
May, L., Scammells, P., Wang, B. & White, P.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/15 → 31/12/17
Project: Research
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Allosteric Fingerprinting of G Protein-Coupled Receptor Monomers and Oligomers
Australian Research Council (ARC)
1/01/13 → 16/11/16
Project: Research
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Prevention and treatment of chronic heart and kidney disease via epidemiological, pharmacological device and cell-based approaches
Krum, H., Kelly, D. & Reid, C.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/10 → 31/12/14
Project: Research