The Soluble Guanylyl Cyclase Activator Bay 58-2667 Selectively Limits Cardiomyocyte Hypertrophy

Abstract

BackgroundAlthough 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.MethodsNeonatal rat cardiomyocytes were incubated with endothelin-1 (ET1, 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.ResultsWe now demonstrate that BAY 58-2667 (0.01–0.3 µmol/L) elicited concentration-dependent antihypertrophic actions, inhibiting ET1-mediated increases in cardiomyocyte 2D area and de novo protein synthesis, as well as suppressing ET1-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.ConclusionsOur 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.

Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFβ signalling

“…By using knockout experiments, we confirmed that the sGC activity is essential for the antifibrotic effects of sGC stimulators. In our experiments with cultured dermal fibroblasts, sGC signalling did not inhibit the release of TGFβ as suggested for chronic heart remodelling and heart fibrosis 17 37 38. By contrast, sGC signalling interfered with non-canonical TGFβ cascades since the antifibrotic effects of the sGC were independent from SMAD2 and 3 signalling and TGFβ target gene transcription.…”

Optimum AT1 receptor-neprilysin inhibition has superior cardioprotective effects compared with AT1 receptor blockade alone in hypertensive rats

“…Indeed, in combination with the high thiorphan dose, this even resulted in a significant decrease in circulating cGMP. Given the physiological antagonism between cGMP and ET-1, for example, with regard to cardiac hypertrophy, 25 this phenomenon may underlie the absence of favorable cardiac effects when combining irbesartan with the high thiorphan dose.…”

A szolubilis guanilát-cikláz aktivátor cinaciguat megelőzi a kardiális diszfunkció kialakulását 1-es típusú cukorbetegség patkánymodelljében

“…Irodalmi adatok szerint az sGC aktivátor cinaciguat (BAY 58-2667) az sGC NO-ra érzéketlen formájának hemkötő zsebéhez kapcsolódik, így helyreállítja annak cGMP-termelését (15). Újabb tanulmányok a cinaciguat jótékony hatását bizonyították miokardiális infarktus (16), miokardiális iszkémiás-reperfúziós károsodás modelljeiben (17, 18), nitro-oxidatív stressz által indukált endothelialis diszfunkcióban (19), vaszkuláris neointima-képződés esetén (20) és a patológiás szívizom-hipertrófi a megelő-zésében (21). A cinaciguat biztonságosságát és tolerálhatóságát humán klinikai vizsgálatokban (fázis I.)…”