Pharmacokinetics and cardioprotective efficacy of intravenous miR-125b* microRNA mimic in a mouse model of acute myocardial infarction.

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY British Journal of Pharmacology Pub Date : 2024-10-29 DOI:10.1111/bph.17345
Tamara Szabados, András Makkos, Bence Ágg, Bettina Benczik, Gábor G Brenner, Márta Szabó, Barnabás Váradi, Imre Vörös, Kamilla Gömöri, Zoltán V Varga, Anikó Görbe, Péter Bencsik, Péter Ferdinandy
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引用次数: 0

Abstract

Background and purpose: MicroRNA (miRNA) therapy is a promising approach to induce cardioprotection. We have previously identified cardiac microRNA-125b* (microRNA-125b-2-3p; miR-125b*) as a potential cardioprotective miRNA, termed ProtectomiR. We aimed to characterize the pharmacokinetics and pharmacodynamics, and the effect of miR-125b* mimic on infarct size using an in vivo mouse model.

Experimental approach: To characterize the pharmacokinetics properties of miR-125b* mimic, a single injection of 10-μg miR-125b* mimic or its scramble miRNA control, or vehicle i.v. was given to C57BL/6 mice. MiR-125b* expression was measured from plasma, heart, kidney and liver samples. Effect of miR-125b* on area at risk and infarct size was assessed after 45-min coronary occlusion, followed by 24-h reperfusion; 10-μg miR-125b* mimic or 10-μg non-targeting miRNA mimic control or vehicle were administered via the right jugular vein at 10th mins of coronary occlusion. To assess molecular mechanism involved in cardioprotection, expression of mRNA targets of miR-125b* were measured from ventricular myocardium at 1, 2, 4, 8 or 24 h post-treatment using quantitative real time polymerase chain reaction.

Key results: MiR-125b* expression was markedly increased in plasma and myocardium 1 h, and in the liver 2h after treatment. Infarct size was significantly reduced after miR-125b* mimic treatment when compared to the vehicle. The expression of Ccna2, Eef2k and Cacnb2 target mRNAs was significantly reduced 8 h after injection of miR-125b* mimic.

Conclusion and implications: This is the first demonstration of pharmacokinetic and molecular pharmacodynamic properties as well as the cardioprotective effect of miR-125b* mimic in vivo.

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急性心肌梗死小鼠模型中静脉注射 miR-125b* 微核糖核酸模拟物的药代动力学和心脏保护功效。
背景和目的:微RNA(miRNA)疗法是诱导心脏保护的一种很有前景的方法。我们之前已发现心脏微RNA-125b*(microRNA-125b-2-3p;miR-125b*)是一种潜在的心脏保护性miRNA,被称为ProtectomiR。我们的目的是利用体内小鼠模型,研究miR-125b*的药代动力学和药效学特征,以及miR-125b*模拟物对梗死面积的影响:为了鉴定 miR-125b* mimic 的药代动力学特性,给 C57BL/6 小鼠静脉注射一次 10-μg miR-125b* mimic 或其扰乱 miRNA 对照或载体。测量血浆、心脏、肾脏和肝脏样本中 MiR-125b* 的表达。在冠状动脉闭塞 45 分钟、再灌注 24 小时后,评估 miR-125b* 对危险面积和梗死面积的影响;在冠状动脉闭塞 10 分钟后,通过右颈静脉注射 10μg miR-125b* mimic 或 10μg 非靶向 miRNA mimic 对照组或载体。为了评估参与心脏保护的分子机制,使用定量实时聚合酶链反应法测定了治疗后 1、2、4、8 或 24 小时心室心肌中 miR-125b* 靶标 mRNA 的表达:主要结果:治疗后 1 小时,血浆和心肌中的 MiR-125b* 表达明显增加,2 小时后肝脏中的表达也明显增加。与药物相比,miR-125b*模拟物治疗后梗死面积明显缩小。注射 miR-125b* mimic 8 小时后,Ccna2、Eef2k 和 Cacnb2 靶 mRNA 的表达明显减少:这是首次证明 miR-125b* mimic 在体内的药代动力学和分子药效学特性以及对心脏的保护作用。
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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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