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Abstract：
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
目的：G蛋白偶联雌激素受体30（GPR30）的激动剂激活，G1在患有心力衰竭（HF）的女性中表现出有益的作用。最近的证据表明，它的心血管益处也可能包括男性。然而,GPR30激活是否以及如何限制HF进展并在男性中发挥有益作用尚不清楚.我们假设慢性G1治疗改善LV和心肌细胞功能，[Ca2+]i调节和β-肾上腺素能储备，从而限制了男性的HF进展。
方法：我们比较了左心室（LV）和肌细胞功能，在对照雄性小鼠(12/组)和异丙肾上腺素诱导的HF(150mg/kgs.c.持续2天)中的[Ca2+]i瞬时([Ca2+]iT)和β-AR调节。注射异丙肾上腺素两周后，HF小鼠接受安慰剂，或G1（150μg/kg/天皮下微型泵）持续2周。
结果：异丙肾上腺素治疗的小鼠在2周时表现出射血分数（HFpEF）保留的HF，并在4周时发展为EF（HFrEF）降低的HF，表现为弛豫的LV时间常数(τ)显著增加，降低EF和二尖瓣流量（dV/dtmax），伴随着减少的肌细胞收缩（dL/dtmax），弛豫(dR/dtmax)和[Ca2+]iT。急性异丙肾上腺素-超融合引起dL/dtmax显著较小的增加，dR/dtmax和[Ca2+]iT。HF中的G1治疗增加了EES的EF和LV收缩性的基础和异丙肾上腺素刺激的增加。重要的是,G1改善了基础和异丙肾上腺素刺激的dL/dtmax，dR/dtmax和[Ca2+]iT控制水平并恢复正常心脏β-AR亚型调制。
结论：慢性G1治疗可恢复正常的基础肌细胞和β-AR刺激的收缩，放松,和[Ca2+]iT，从而逆转LV功能障碍并在HF的雄性小鼠模型中发挥挽救作用。
方法：我们比较了左心室（LV）和肌细胞功能，在对照雄性小鼠(12/组)和异丙肾上腺素诱导的HF(150mg/kgs.c.持续2天)中的[Ca2+]i瞬时([Ca2+]iT)和β-AR调节。注射异丙肾上腺素两周后，HF小鼠接受安慰剂，或G1（150μg/kg/天皮下微型泵）持续2周。
结果：异丙肾上腺素治疗的小鼠在2周时表现出射血分数（HFpEF）保留的HF，并在4周时发展为EF（HFrEF）降低的HF，表现为弛豫的LV时间常数(τ)显著增加，降低EF和二尖瓣流量（dV/dtmax），伴随着减少的肌细胞收缩（dL/dtmax），弛豫(dR/dtmax)和[Ca2+]iT。急性异丙肾上腺素-超融合引起dL/dtmax显著较小的增加，dR/dtmax和[Ca2+]iT。HF中的G1治疗增加了EES的EF和LV收缩性的基础和异丙肾上腺素刺激的增加。重要的是,G1改善了基础和异丙肾上腺素刺激的dL/dtmax，dR/dtmax和[Ca2+]iT控制水平并恢复正常心脏β-AR亚型调制。
结论：慢性G1治疗可恢复正常的基础肌细胞和β-AR刺激的收缩，放松,和[Ca2+]iT，从而逆转LV功能障碍并在HF的雄性小鼠模型中发挥挽救作用。
