Abstract 12559: Chronic GPER Activation Attenuates Cardiac Dysfunction in a Male Mouse Model of Progressive Heart Failure: Insights Into Cellular Mechanisms

Abstract

Background: Activation of G protein-coupled estrogen receptor, GPER, has been shown to exhibit beneficial actions in several cardiovascular diseases, including heart failure (HF). While reports on GPER have highlighted mostly female sex-specific health issues, recent evidence indicates its cardiovascular benefits may include the opposite sex. However, the exact means by which GPER affords cardioprotection are unclear. Moreover whether and how GPER activation may limit HF progression and have a salutary role in males is unknown. We tested the hypothesis that chronic GPER activation by its specific agonist G 1 improves myocyte function and [Ca 2+ ] i regulation, thus limiting HF progression in male mice. Methods: We simultaneously examined LV and myocyte function and [Ca 2+ ] i transient ([Ca 2+ ] iT ) responses in 3 groups of male mice (11/group) over 4 weeks (W): HF receiving the initial injection of isoproterenol (ISO) (150 mg/kg sq for 2 days) over 2 W, then receiving placebo; HF/G 1 after ISO for 2W, then receiving G 1 (150 μg /kg/day sq via mini pump), given for 2W; and controls . Results: Compared with controls, both Echo and hemodynamic assessments revealed that ISO-treated mice had HFpEF onset at 2 W after ISO and progressed to mild HF at 4 W with LV dilatation, increased LV time constant of relaxation (τ) (5.4 vs 3.1 ms), and 52% reductions in peak rate of mitral flow (dV/dt max ); accompanied by significantly reduced myocyte contraction (dL/dt max , 102.7 vs 143.6 μm/s), relaxation (dR/dt max ,69.9 vs 107.9 μm/s) and [Ca 2+ ] iT (0.16 vs 0.21). Importantly, compared with normal myocytes, ISO (10 -8 M) caused significantly less increases in dL/dt max (24% vs 61%), dR/dt max (23% vs 57%), and [Ca 2+ ] iT (15% vs 30%) in HF myocytes. HF/G1 rats, compared to HF, showed significantly increased LV dV/dt max and decreased t (4.0 ms) accompanied by increased dL/dt max (142.6 μm/s), dR/dt max (107.9 μm/s) and [Ca 2+ ] iT (0.21). Moreover, ISO-induced increases in dL/dt max (61%), dR/dt max (56%), and [Ca 2+ ] iT (30%) in myocytes from HF/G 1 were significantly augmented, similar to controls. Conclusions: Chronic G 1 treatment restores normal myocyte basal and β-AR stimulated contraction, relaxation and [Ca 2+ ] i regulation, leading to regression of LV dysfunction in a male mouse model of HF.