Abstract 12592: Targeted Delivery of AntimiR-23a Using Ultrasound and Microbubbles Suppresses Cardiac Hypertrophy and Improves Cardiac Function in vivo
Background: MicroRNAs (miRs) are dysregulated in various cardiovascular diseases. An antimiR against miR-23a suppressed hypertension-induced cardiac hypertrophy in preclinical models, but clinical translation is limited by a lack of cardiac-targeted delivery systems. Ultrasound-targeted microbubble (MB) destruction (UTMD) is a novel therapeutic delivery platform that utilizes MBs as nucleic acid carriers and offers a non-invasive image-guided approach to target delivery of molecular therapeutics to the heart. We hypothesized that cardiac delivery of an antimiR against miR-23a using UTMD suppresses cardiac hypertrophy and improves cardiac function in hypertensive mice.
Methods: Cationic lipid MBs were loaded with negative control antimiR (NC) or antimiR-23a. C57BL/6 mice were implanted with phenylephrine-loaded osmotic minipumps (100 mg/kg/d) and received UTMD treatments (1.3 MHz, MI setting=1.0) with 300 pmol antimiR 0, 3, and 7 days later. A third group (no phenylephrine, No-PE) of age matched mice received no treatments. At 2 weeks, miR-23a levels were measured using RT-PCR. Left ventricular (LV) mass and function were serially assessed with echocardiography.
Results: UTMD treatment with antimiR-23a knocked down cardiac miR-23a by 41 ± 8% compared to UTMD treatment with NC (n=8-9/group, p<0.01). As expected, phenylephrine increased LV mass relative to No-PE mice. However, compared to treatment with UTMD + NC, LV mass in mice with UTMD + antimiR-23a was 16 ± 2% lower after 1 week (p < 0.05), and remained lower during the study (p=0.06) (Figure 1). By 2 weeks, fractional shortening had decreased in UTMD + NC but was preserved in UTMD + antimiR-23a (45.2% vs. 37.7%, p < 0.05).
Conclusions: To our knowledge, this is the first study to demonstrate suppression of cardiac hypertrophy and preservation of cardiac function with UTMD-targeted delivery of a miRNA inhibitor. Our data suggest that UTMD could be used to deliver other miRNA therapeutics for cardiac therapy.
Author Disclosures: J.A. Kopechek: None. C.F. McTiernan: None. X. Chen: None. R. Feroze: None. B. Qin: None. J. Cyriac: None. L. Lavery: None. D. Whitehurst: None. F.S. Villanueva: None.
- © 2016 by American Heart Association, Inc.