Key result
Intravenous miR-125b* mimic significantly reduces myocardial infarct size compared to vehicle in preclinical testing.
Why the study?
Although miR-125b* was previously identified as a potential cardioprotective ProtectomiR, its pharmacokinetics, pharmacodynamics, and effect on infarct size remained to be characterized in vivo.
Does intravenous miR-125b* mimic reduce infarct size in a mouse model of acute myocardial infarction?
Does intravenous miR-125b* mimic reduce infarct size in a mouse model of acute myocardial infarction?
Intravenous administration of miR-125b* mimic significantly reduces infarct size in a mouse model of acute myocardial infarction, demonstrating its potential as a cardioprotective RNA therapeutic.
Supports hypothesis generation for miRNA mimics in cardioprotection; leaves open translation from mouse models to human acute myocardial infarction.
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. LINKED ARTICLES: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc.
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Szabados et al. (2024) studied Acute Myocardial Infarction. miR-125b* mimic vs. Vehicle and scrambled/non-targeting miRNA was evaluated on Infarct size. Intravenous miR-125b* mimic significantly reduced infarct size compared to vehicle in a mouse model of acute myocardial infarction.
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