期刊
JOURNAL OF THE AMERICAN HEART ASSOCIATION
卷 3, 期 5, 页码 -出版社
WILEY
DOI: 10.1161/JAHA.114.000946
关键词
Angiogenesis; antagomir; heart failure; microRNA; myocardial infarction; remodeling
资金
- Spanish Ministry of Science [SAF 2008/03067]
- Carlos III Institute of Health (Cardiovascular Research Network) [RD12/0042/0021, PI12/00788, PI12/01738]
- Spanish Society of Cardiology
- Ulysses
Background-Small and large preclinical animal models have shown that antagomir-92a-based therapy reduces early postischemic loss of function, but its effect on postinfarction remodeling is not known. In addition, the reported remote miR-92a inhibition in noncardiac organs prevents the translation of nonvectorized miR-targeted therapy to the clinical setting. We investigated whether a single intracoronary administration of antagomir-92a encapsulated in microspheres could prevent deleterious remodeling of myocardium 1 month after acute myocardial infarction AUTHOR: Should acute be added before myocardial infarction (since abbreviation is AMI)? Also check at first mention in main text (AMI) without adverse effects. Methods and Results-In a percutaneous pig model of reperfused AMI, a single intracoronary administration of antagomir-92a encapsulated in specific microspheres (9 mu m poly-D,-lactide-co-glycolide [PLGA]) inhibited miR-92a in a local, selective, and sustained manner (n=3 pigs euthanized 1, 3, and 10 days after treatment; 8x, 2x, and 5x-fold inhibition at 1, 3, and 10 days). Downregulation of miR-92a resulted in significant vessel growth (n=27 adult minipigs randomly allocated to blind receive encapsulated antagomir-92a, encapsulated placebo, or saline [n=8, 9, 9]; P=0.001), reduced regional wall-motion dysfunction (P=0.03), and prevented adverse remodeling in the infarct area 1 month after injury (P=0.03). Intracoronary injection of microspheres had no significant adverse effect in downstream myocardium in healthy pigs (n=2), and fluorescein isothiocyanate albumin-PLGA microspheres were not found in myocardium outside the left anterior descending coronary artery territory (n=4) or in other organs (n=2). Conclusions-Early single intracoronary administration of encapsulated antagomir-92a in an adult pig model of reperfused AMI prevents left ventricular remodeling with no local or distant adverse effects, emerging as a promising therapeutic approach to translate to patients who suffer a large AMI.
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