Gpr55 deficiency crucially alters cardiomyocyte homeostasis and counteracts angiotensin II induced maladaption in female mice.

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Brigitte Schopohl, Michael Kohlhaas, Alexander G Nickel, Anna-Florentine Schiuma, Sanne L Maas, Emiel P C van der Vorst, Yi Xuan Shia, Christoph Maack, Sabine Steffens, Sarah-Lena Puhl
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引用次数: 0

Abstract

Background and purpose: Cannabis stimulates several G-protein-coupled-receptors and causes bradycardia and hypotension upon sustained consumption. Moreover, in vitro studies suggest an interference of cannabinoid-signalling with cardiomyocyte contractility and hypertrophy. We aimed at revealing a functional contribution of the cannabinoid-sensitive receptor GPR55 to cardiomyocyte homeostasis and neurohumorally induced hypertrophy in vivo.

Experimental approach: Gpr55-/- and wild-type (WT) mice were characterized after 28-day angiotensin II (AngII; 1·μg·kg-1 min-1) or vehicle infusion. In isolated adult Gpr55-/- and WT cardiomyocytes, mitochondrial function was assessed under naïve conditions, while cytosolic Ca2+ handling was additionally determined following application of the selective GPR55 antagonist CID16020046.

Key results: Gpr55 deficiency did not affect angiotensin II (AngII) mediated hypertrophic growth, yet, especially in females, it alleviated maladaptive pro-hypertrophic and -inflammatory gene expression and improved inotropy and adrenergic responsiveness compared to WT. In-depth analyses implied increased cytosolic Ca2+ concentrations and transient amplitudes, and accelerated sarcomere contraction kinetics in Gpr55-/- myocytes, which could be mimicked by GPR55 blockade with CID16020046 in female WT cells. Moreover, Gpr55 deficiency up-regulated factors involved in glucose and fatty acid transport independent of the AngII challenge, accelerated basal mitochondrial respiration and reduced basal protein kinase (PK) A, G and C activity and phospholemman (PLM) phosphorylation.

Conclusions and implications: Our study suggests GPR55 as crucial regulator of cardiomyocyte hypertrophy and homeostasis presumably by regulating PKC/PKA-PLM and PKG signalling, and identifies the receptor as potential target to counteract maladaptation, adrenergic desensitization and metabolic shifts as unfavourable features of the hypertrophied heart in females.

Gpr55 缺乏症严重改变了雌性小鼠心肌细胞的稳态,并抵消了血管紧张素 II 诱导的适应不良。
背景和目的:大麻会刺激多个 G 蛋白偶联受体,持续吸食会导致心动过缓和低血压。此外,体外研究表明,大麻素信号会干扰心肌细胞的收缩力和肥大。我们的目的是揭示大麻素敏感受体 GPR55 对体内心肌细胞稳态和神经休克诱导的肥大的功能性贡献:实验方法:在输注血管紧张素 II(AngII;1-μg-kg-1 min-1)或药物 28 天后,对 Gpr55-/- 和野生型(WT)小鼠进行表征。在分离的成年 Gpr55-/- 和 WT 心肌细胞中,评估了线粒体在原始条件下的功能,并在应用选择性 GPR55 拮抗剂 CID16020046 后测定了细胞膜 Ca2+ 处理:主要结果:与 WT 相比,GPR55 缺乏并不影响血管紧张素 II(AngII)介导的肥厚性生长,但与 WT 相比,GPR55 缺乏可减轻不良的促肥厚性和炎症基因表达,并改善肌力和肾上腺素能反应性,尤其是在雌性中。深入分析表明,Gpr55-/-肌细胞的细胞膜Ca2+浓度和瞬时幅度增加,肌节收缩动力学加快,而在雌性WT细胞中,用CID16020046阻断GPR55可以模拟这种情况。此外,Gpr55 缺乏会上调参与葡萄糖和脂肪酸转运的因子,与 AngII 挑战无关,加速基础线粒体呼吸,降低基础蛋白激酶(PK)A、G 和 C 活性及磷脂酰亚胺(PLM)磷酸化:我们的研究表明,GPR55 可能通过调节 PKC/PKA-PLM 和 PKG 信号,成为心肌细胞肥大和稳态的关键调节因子,并将该受体确定为潜在靶点,以对抗女性肥大心脏的不利特征--适应不良、肾上腺素能脱敏和代谢转变。
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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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