Abstract 829: Endothelial Estrogen Non-nuclear Signaling Plays a Key Role in Anti-remodeling Effects via cGMP Signaling in Failing Heart

Abstract

Background: Estrogen plays a significant role in cardiovascular benefits. As one of its beneficial pathways, ERα non-nuclear signaling is known to be protective for the vascular system, but its role for cardiac remodeling is unknown thus far. We previously reported cGMP pathways are one of the critical therapeutic targets for heart failure and ERα non-nuclear signaling played a pivotal role in cardioprotection and was indispensable to the therapeutic efficacy of cGMP-PDE5 inhibition. However, it is still remaining undetermined which cells are playing the key role in cardioprotective effects via ERα non-nuclear signaling. Methods: We generated genetically modified mouse lacking ERα in cardiomyocytes (ERα f/f /αMHC Cre/+ ) or endothelial cells (ERα f/f /Tie2 Cre/+ ) and assessed the effects of chronic pressure-overload (TAC) and the efficacy of PDE5 inhibitor (PDE5i) sildenafil after TAC. In addition, for the first time we generated endothelial cell specific genet-modified mouse lacking interactions between p85α and ERα which are critical for non-nuclear signaling (ERα KI/KI /Tie2 Cre/+ ). Cardiac functions were assessed for evaluating the effects of endothelial ERα non-nuclear singlaing to failing hearts. Results: Under physiological E2 status, PDE5i’s anti-remodeling effects after TAC were abrogated in ERα f/f /Tie2 Cre/+ (FS(%) ± SEM with vs without PDE5i 28.16 ± 3.43 vs 31.87 ± 2.30) but not in ERα f/f /αMHC Cre/+ (FS(%) ± SEM with PDE5i vs without PDE5i 54.57 ± 3.418 vs 43.3 ± 1.21) consistent with hemodynamic analysis. Assessment with ERα KI/KI /Tie2 Cre/+ showed decreased cardiac functions even with physiological E2. Hemodynamic analysis also supported the cardioprotective effects of ERα non-nuclear signaling in endothelial cells. Conclusion: ERα non-nuclear reaction in endothelial cells plays an important role in cardio-protective mechanism, and endothelial estrogen signals are indispensable to the therapeutic efficacy of cGMP-PDE5 inhibition. Our results clarified one of the cardioprotective signals of estrogen and highlighted the new strategy for heart failure treatment.