The activated caveolin-3/μ-opioid receptor complex drives morphine-induced rescue therapy in failing hearts.

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Chengxiao Guo, Xinxin Pan, Mengyun Dou, Juan Wu, Xinyu Chen, Baoli Wang, Rui Zhu, Shijin Xu, Wenyi Peng, Chao Wu, Shufang He, Sihe Zhang, Ye Zhang, Shiyun Jin
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引用次数: 0

Abstract

Background and purpose: Opioid analgesics can alleviate ischaemia/reperfusion (I/R) injury in chronic heart failure. However, the underlying mechanisms and targets remain unknown. Here, we investigate if caveolin-3 (Cav3) interacts with μ opioid receptors and if Cav3-μ receptor interactions play a role in morphine-induced cardioprotection in failing hearts.

Experimental approach: Cav3 and μ receptor proteins in human and rat heart tissue were determined by western blot, immunofluorescence and co-immunoprecipitation. Methyl-β-cyclodextrin (MβCD), a destroyer of caveolae, and AAV-Cav3 shRNA were used to reduce Cav3 expression in failing rat hearts. CTOP, a specific μ antagonist, was administrated before morphine preconditioning in perfused failing heart models of myocardial I/R injury.

Key results: Levels of Cav3 and μ receptor proteins were significantly higher in human and rat myocardial tissues with heart failure than in control tissues. Cav3 and μ receptor expression levels were positively correlated with disease severity. The signal of the cardiac Cav3 protein was colocalized with μ receptor in both the human and rat heart sections. Disruption of caveolae in the failing heart by either MβCD or AAV-Cav3 shRNA significantly inhibits morphine-induced phosphorylation of ERK1/2 and cardioprotection. Administration of CTOP substantially reduced Cav3 expression and morphine-induced cardioprotective effect in heart failure.

Conclusion and implications: Our data suggest that up-regulation of the Cav3/μ receptor complex is critical for morphine protection of the failing heart against I/R injury by regulating the ERK1/2 pathway. The activated Cav3/μ receptor complex is an understudied therapeutic target for opioid treatment of heart failure and ischaemic insult.

激活的洞穴素-3/μ-阿片受体复合物推动了吗啡诱导的衰竭心脏抢救疗法。
背景和目的:阿片类镇痛药可减轻慢性心力衰竭的缺血再灌注(I/R)损伤。然而,其潜在的机制和靶点仍然未知。在此,我们研究了洞穴素-3(Cav3)是否与μ阿片受体相互作用,以及Cav3-μ受体相互作用是否在吗啡诱导的心衰心脏保护中发挥作用:实验方法:通过Western印迹、免疫荧光和共免疫沉淀法测定人和大鼠心脏组织中的Cav3和μ受体蛋白。使用洞穴破坏剂甲基-β-环糊精(MβCD)和 AAV-Cav3 shRNA 减少衰竭大鼠心脏中 Cav3 的表达。在心肌I/R损伤的灌注衰竭心脏模型中,在吗啡预处理前给予特异性μ拮抗剂CTOP:主要结果:人和大鼠心力衰竭心肌组织中的Cav3和μ受体蛋白水平明显高于对照组织。Cav3和μ受体表达水平与疾病严重程度呈正相关。在人和大鼠的心脏切片中,心脏Cav3蛋白的信号与μ受体共定位。通过MβCD或AAV-Cav3 shRNA破坏衰竭心脏中的腔隙,可显著抑制吗啡诱导的ERK1/2磷酸化和心脏保护作用。CTOP可大幅降低Cav3的表达,并降低吗啡诱导的心衰患者心脏保护作用:我们的数据表明,Cav3/μ受体复合物的上调对于吗啡通过调节ERK1/2途径保护衰竭心脏免受I/R损伤至关重要。活化的Cav3/μ受体复合物是阿片类药物治疗心衰和缺血性损伤的一个未被充分研究的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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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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