title: VCP746, a novel A1 adenosine receptor biased agonist, reduces hypertrophy in a rat neonatal cardiac myocyte model.
abstract: VCP746 is a novel A1 adenosine receptor (A1 AR) 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 (3) H-leucine incorporation assay. VCP746 significantly inhibited IL-1β-, TNF-α- and Ang II-stimulated NCM hypertrophy as determined by (3) H-leucine incorporation. The anti-hypertrophic effect of VCP746 was also more potent than that of the prototypical A1 AR agonist, N(6) -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 (3) H-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 A1 AR 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.
authors.affiliation: Drug Discovery Biology, Monash University, Parkville, Vic., Australia.
authors.forename: Chung H
authors.initials: CH
authors.lastname: Chuo
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Vic., Australia.
authors.forename: Shane M
authors.initials: SM
authors.lastname: Devine
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Vic., Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scammells
authors.affiliation: Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic., Australia.
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
authors.affiliation: Drug Discovery Biology, Monash University, Parkville, Vic., Australia.
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.affiliation: Drug Discovery Biology, Monash University, Parkville, Vic., Australia.
authors.forename: Lauren T
authors.initials: LT
authors.lastname: May
authors.affiliation: Drug Discovery Biology, Monash University, Parkville, Vic., Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: White
authors.affiliation: Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic., Australia.
authors.forename: Bing H
authors.initials: BH
authors.lastname: Wang
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D058907:Adenosine A1 Receptor Agonists; D013876:Thiophenes; C000618341:VCP746; D000241:Adenosine
keywords: adenosine A1-receptor; adenosine receptors; cardiomyocyte; cardiomyocyte hypertrophy; cardiovascular pharmacology