Abstract 15291: The Soluble Guanylyl Cyclase (sGC) Activator BAY 58-2667 Selectively Limits Cardiomyocyte Hypertrophy - A Potential Therapeutic Advantage for Managing Left Ventricular Hypertrophy (LVH)
Evidence suggests cGMP is a negative regulator of LVH. Traditional nitrovasodilators are not indicated for managing LVH, due to the combined phenomena of nitrate tolerance as well as NO• resistance, both in part due to oxidative stress. The direct consequences of the NO•-independent sGC activator BAY 58-2667 on LV remodeling, independent of hemodynamic load, have however not been investigated. We tested the hypothesis that BAY 58-2667 directly inhibits cardiomyocyte hypertrophy in vitro. Concomitant impact of BAY 58-2667 on fibroblast proliferation, and insights into potential mechanisms of action, were also sought. Results were compared to the sGC stimulator BAY 41-2272. BAY 58-2667 (0.01-0.30µM, 48h) elicited concentration-dependent antihypertrophic actions in neonatal rat cardiomyocytes, inhibiting endothelin-1 (ET1, 60nM)-mediated increases in cell size and de novo protein synthesis, as well as suppressing ET1-induced cardiomyocyte superoxide (•O2-) generation. This was accompanied by markedly increased cardiomyocyte cGMP as well as activity of its downstream biomarker, vasodilator-stimulated phosphoprotein, without elevating cAMP. In contrast, submicromolar concentrations of BAY 58-2667 had no effect on basal or serum-stimulated neonatal rat cardiac fibroblast proliferation. Indeed, only at concentrations >10µM was fibrosis inhibited in either context. The majority of BAY 58-2667 effects were mimicked by BAY 41-2272, with the exception of •O2- suppression. BAY 41-2272 was also a less potent sGC stimulator in both cell types. Cardiomyocyte responses to BAY 58-2667 (but not BAY 41-2272) were enhanced by the sGC oxidizing agent, ODQ (10µM). In conclusion, 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. Given that this distinctive sGC ligand can both suppress cardiomyocyte •O2- and activate sGC in its oxidized form in cardiomyocytes (a distinct advantage over nitrovasodilators or sGC stimulators such as BAY 41-2272 and NO•), BAY 58-2667 may potentially represent an alternative therapeutic approach for limiting LVH.
- © 2012 by American Heart Association, Inc.