Aims

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.

Main 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.

Key findings

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/dt_max), which were accompanied by reduced myocyte contraction (dL/dt_max), relaxation (dR/dt_max) and [Ca²⁺]_iT. Acute isoproterenol-superfusion caused significantly smaller increases in dL/dt_max, dR/dt_max and [Ca²⁺]_iT. G1 treatment in HF increased basal and isoproterenol-stimulated increases in EF and LV contractility of E_ES. Importantly, G1 improved basal and isoproterenol-stimulated dL/dt_max, dR/dt_max and [Ca²⁺]_iT to control levels and restored normal cardiac β-AR subtypes modulation.

Significance

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.

中文翻译：

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慢性 GPR30 激动剂治疗可在进行性心力衰竭的雄性小鼠模型中恢复正常心脏功能表现：对细胞机制的洞察

宗旨

G 蛋白偶联雌激素受体 30 (GPR30) 被其激动剂 G1 激活，对患有心力衰竭 (HF) 的女性表现出有益作用。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 治疗可改善 LV 和心肌细胞功能、[Ca ²⁺ ] _i调节和 β-肾上腺素能储备，从而限制男性的 HF 进展。

主要方法

我们比较了左心室 (LV) 和肌细胞功能、[Ca ²⁺ ] _i瞬态 ([Ca ²⁺ ] _iT ) 和 β-AR 调节在对照雄性小鼠 (12/组) 和异丙肾上腺素诱导的 HF (150 mg/kg sc 2 天）。注射异丙肾上腺素两周后，HF 小鼠接受安慰剂或 G1（150 μg/kg/天皮下微型泵）2 周。

主要发现

异丙肾上腺素治疗的小鼠在 2 周时表现出射血分数保留 (HFpEF) 的 HF，并在 4 周时进展为 HF 并伴有 EF 降低 (HFrEF)，表现为 LV 舒张时间常数 (τ) 显着增加、EF 和二尖瓣流量降低(dV/dt _max )，伴随着肌细胞收缩 (dL/dt _max )、松弛 (dR/dt _max ) 和 [Ca ²⁺ ] _{iT 减少}。急性异丙肾上腺素灌注导致 dL/dt _max、dR/dt _max和 [Ca ²⁺ ] _{iT 的}显着增加较小。HF 中的 G1 治疗增加了基础和异丙肾上腺素刺激的 EF 和 E _{ES 的}LV 收缩性增加. 重要的是，G1 改善了基础和异丙肾上腺素刺激的 dL/dt _max、dR/dt _max和 [Ca ²⁺ ] _iT以控制水平并恢复正常的心脏 β-AR 亚型调制。

意义

慢性 G1 治疗可恢复正常的心肌细胞基础和 β-AR 刺激的收缩、松弛和 [Ca ²⁺ ] _iT，从而逆转 LV 功能障碍并在雄性 HF 小鼠模型中发挥挽救作用。