Chronic GPR30 agonist therapy causes restoration of normal cardiac functional performance in a male mouse model of progressive heart failure: Insights into cellular mechanisms

G protein-coupled estrogen receptor 30 (GPR30) activation by its agonist, G1, exhibits beneficial actions in female with heart failure (HF). Recent evidence indicates its cardiovascular benefits may also include male as well. However, whether and how GPR30 activation may limit HF progression and have a salutary role in males is unknown. We hypothesized that chronic G1 treatment improves LV and cardiomyocyte function, [Ca2+]i regulation and β-adrenergic reserve, thus limiting HF progression in male. We compared left ventricle (LV) and myocyte function, [Ca2+]i transient ([Ca2+]iT) and β-AR modulation in control male mice (12/group) and isoproterenol-induced HF (150 mg/kg s.c. for 2 days). Two weeks after isoproterenol injection, HF mice received placebo, or G1 (150 μg/kg/day s.c. mini-pump) for 2 weeks. Isoproterenol-treated mice exhibited HF with preserved ejection fraction (HFpEF) at 2-weeks and progressed to HF with reduced EF (HFrEF) at 4-weeks, manifested by significantly increased LV time constant of relaxation (τ), decreased EF and mitral flow (dV/dtmax), which were accompanied by reduced myocyte contraction (dL/dtmax), relaxation (dR/dtmax) and [Ca2+]iT. Acute isoproterenol-superfusion caused significantly smaller increases in dL/dtmax, dR/dtmax and [Ca2+]iT. G1 treatment in HF increased basal and isoproterenol-stimulated increases in EF and LV contractility of EES. Importantly, G1 improved basal and isoproterenol-stimulated dL/dtmax, dR/dtmax and [Ca2+]iT to control levels and restored normal cardiac β-AR subtypes modulation. Chronic G1 treatment restores normal myocyte basal and β-AR-stimulated contraction, relaxation, and [Ca2+]iT, thereby reversing LV dysfunction and playing a rescue role in a male mouse model of HF.