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

LIFE SCIENCES

卷:285

Article

Zhang, Xiaowei^1,2  Li, Tiankai^2,3  Cheng, Heng-Jie²  Wang, Hao⁴  Ferrario, Carlos M.⁵  Groban, Leanne⁴  Cheng, Che Ping² 

[1] Shandong Univ, Cheeloo Coll Med, Hosp 2, Dept Cardiol, Jinan, Shandong, Peoples R China

[2] Wake Forest Sch Med, Cardiovasc Med, Med Ctr Blvd, Winston Salem, NC 27157 USA

[3] Harbin Med Univ, Affiliated Hosp 1, Dept Cardiol, Harbin, Peoples R China

[4] Wake Forest Sch Med, Dept Anesthesiol, Winston Salem, NC 27157 USA

[5] Wake Forest Sch Med, Dept Surg, Winston Salem, NC 27157 USA

关键词: G protein-coupled estrogen receptor 30 (GPR30);    Heart failure;    Pressure-volume relation;    Cardiomyocyte;    [Ca2+](i) regulation;    beta-Adrenergic reserve;   

DOI  :  10.1016/j.lfs.2021.119955

来源: Elsevier

【 摘 要 】

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 beta-adrenergic reserve, thus limiting HF progression in male. Main methods: We compared left ventricle (LV) and myocyte function, [Ca2+](i) transient ([Ca2+](iT)) and beta-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 mu g/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 (tau), 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 beta-AR subtypes modulation. Significance: Chronic G1 treatment restores normal myocyte basal and beta-AR-stimulated contraction, relaxation, and [Ca2+](iT), thereby reversing LV dysfunction and playing a rescue role in a male mouse model of HF.

【 授权许可】

Free