title: The soluble guanylyl cyclase activator bay 58-2667 selectively limits cardiomyocyte hypertrophy.
abstract: BACKGROUND
  Although evidence now suggests cGMP is a negative regulator of cardiac hypertrophy, the direct consequences of the soluble guanylyl cyclase (sGC) activator BAY 58-2667 on cardiac remodeling, independent of changes in hemodynamic load, has not been investigated. In the present study, we tested the hypothesis that the NO(•)-independent sGC activator BAY 58-2667 inhibits cardiomyocyte hypertrophy in vitro. Concomitant impact of BAY 58-2667 on cardiac fibroblast proliferation, and insights into potential mechanisms of action, were also sought. Results were compared to the sGC stimulator BAY 41-2272.
  
  
  METHODS
  Neonatal rat cardiomyocytes were incubated with endothelin-1 (ET(1), 60nmol/L) in the presence and absence of BAY 41-2272 and BAY 58-2667 (0.01-0.3 µmol/L). Hypertrophic responses and its triggers, as well as cGMP signaling, were determined. The impact of both sGC ligands on basal and stimulated cardiac fibroblast proliferation in vitro was also determined.
  
  
  RESULTS
  We now demonstrate that BAY 58-2667 (0.01-0.3 µmol/L) elicited concentration-dependent antihypertrophic actions, inhibiting ET(1)-mediated increases in cardiomyocyte 2D area and de novo protein synthesis, as well as suppressing ET(1)-induced cardiomyocyte superoxide generation. This was accompanied by potent increases in cardiomyocyte cGMP accumulation and activity of its downstream signal, vasodilator-stimulated phosphoprotein (VASP), without elevating cardiomyocyte cAMP. In contrast, submicromolar concentrations of BAY 58-2667 had no effect on basal or stimulated cardiac fibroblast proliferation. Indeed, only at concentrations ≥10 µmol/L was inhibition of cardiac fibrosis seen in vitro. The effects of BAY 58-2667 in both cell types were mimicked by BAY 41-2272.
  
  
  CONCLUSIONS
  Our results demonstrate that BAY 58-2667 elicits protective, cardiomyocyte-selective effects in vitro. These actions are associated with sGC activation and are evident in the absence of confounding hemodynamic factors, at low (submicromolar) concentrations. Thus this distinctive sGC ligand may potentially represent an alternative therapeutic approach for limiting myocardial hypertrophy.
authors.affiliation: Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Irvine
authors.forename: Virat
authors.initials: V
authors.lastname: Ganthavee
authors.forename: Jane E
authors.initials: JE
authors.lastname: Love
authors.forename: Amy E
authors.initials: AE
authors.lastname: Alexander
authors.forename: John D
authors.initials: JD
authors.lastname: Horowitz
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Kemp-Harper
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Ritchie
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D006332:Cardiomegaly / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006162:Guanylate Cyclase / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071756:Soluble Guanylyl Cyclase; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D001565:Benzoates; D015815:Cell Adhesion Molecules; D019332:Endothelin-1; D008840:Microfilament Proteins; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D000098662:Vasodilator-Stimulated Phosphoprotein; C480588:BAY 58-2667; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP