An adenosinergic positive feedback loop extends pharmacological cardioprotection duration

IF 6.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology Pub Date : 2024-09-10 DOI:10.1111/bph.17331

Gerald Wölkart, Simon Gissing, Heike Stessel, Erin K. Fassett, Burkhard Klösch, Robert W. Greene, Bernd Mayer, John T. Fassett

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Abstract

Background and Purpose

Adenosine receptor activation induces delayed, sustained cardioprotection against ischaemia–reperfusion (IR) injury (24–72 h), but the mechanisms underlying extended cardioprotection duration remain unresolved. We hypothesized that a positive feedback loop involving adenosine receptor-induced proteasomal degradation of adenosine kinase (ADK) and decreased myocardial adenosine metabolism extends the duration of cardioprotection.

Experimental Approach

Mice were administered an ADK inhibitor, ABT-702, to induce endogenous adenosine signalling. Cardiac ADK protein and mRNA levels were analysed 24–120 h later. Theophylline or bortezomib was administered 24 h after ABT-702 to examine the late roles of adenosine receptors or proteasomal activity, respectively, in ADK expression and cardioprotection at 72 h. Coronary flow and IR tolerance were analysed by Langendorff technique. The potential for continuous adenosinergic cardioprotection was examined using heterozygous, cardiac-specific ADK KO (cADK^+/−) mice. Cardiac ADK expression was also examined after A₁ or A₃ receptor agonist, phenylephrine, lipopolysaccharide or sildenafil administration.

Key results

ABT-702 treatment decreased ADK protein content and provided cardioprotection from 24 to 72 h. ADK mRNA upregulation restored ADK protein after 96–120 h. Adenosine receptor or proteasome inhibition at 24 h reversed ABT-702-induced ADK protein deficit and cardioprotection at 72 h. cADK^+/− hearts exhibited continuous cardioprotection. Diverse preconditioning agents also diminished cardiac ADK protein expression.

Conclusion and Implications

A positive feedback loop driven by adenosine receptor-induced ADK degradation and renewed adenosine signalling extends the duration of cardioprotection by ABT-702 and possibly other preconditioning agents. The therapeutic potential of continuous adenosinergic cardioprotection is demonstrated in cADK^+/− hearts.

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腺苷能正反馈环路延长了药物心脏保护的持续时间

背景和目的腺苷受体激活可诱导针对缺血再灌注（IR）损伤的延迟、持续心脏保护（24-72 h），但延长心脏保护持续时间的机制仍未解决。我们推测，腺苷受体诱导的腺苷酸激酶（ADK）蛋白酶体降解和心肌腺苷代谢减少的正反馈循环可延长心脏保护的持续时间。实验方法给小鼠注射ADK抑制剂ABT-702以诱导内源性腺苷信号传导。24-120 小时后分析心脏 ADK 蛋白和 mRNA 水平。在 ABT-702 24 小时后给小鼠注射茶碱或硼替佐米，分别检测腺苷受体或蛋白酶体活性在 ADK 表达和 72 小时心脏保护中的后期作用。使用杂合子、心脏特异性 ADK KO（cADK+/-）小鼠检验了持续腺苷能心脏保护的潜力。主要结果ABT-702处理可降低ADK蛋白含量，并在24至72小时内提供心脏保护。ADK mRNA上调可在96至120小时后恢复ADK蛋白。由腺苷受体诱导的ADK降解和腺苷信号更新驱动的正反馈环路延长了ABT-702和其他可能的预处理药物的心脏保护持续时间。在 cADK+/- 心脏中证明了持续腺苷能心脏保护的治疗潜力。

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

British Journal of Pharmacology 医学-药学

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.