PloS one · 2012
The soluble guanylyl cyclase activator bay 58-2667 selectively limits cardiomyocyte hypertrophy.
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Irvine Jennifer C, Ganthavee Virat, Love Jane E, Alexander Amy E, Horowitz John D, Stasch Johannes-Peter, Kemp-Harper Barbara K, Ritchie Rebecca H
Аннотация
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.
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.
Предметные рубрики MeSH
AnimalsBenzoatesCardiomegalyCell Adhesion MoleculesCells, CulturedCyclic GMPEndothelin-1Enzyme ActivationFibroblastsGuanylate CyclaseMicrofilament ProteinsMyocytes, CardiacPhosphoproteinsRatsRats, Sprague-DawleyReactive Oxygen SpeciesReceptors, Cytoplasmic and NuclearSignal TransductionSoluble Guanylyl CyclaseVasodilator-Stimulated Phosphoprotein