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

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.