Abstract 13719: Delivery of microRNA-145 Restores Coronary Collateral Growth in Metabolic Syndrome Rats
In response to transient, repetitive coronary artery occlusion, small arterioles enlarge into conduit arteries by coronary collateral growth (CCG). In the early stages of CCG, vascular smooth muscle cells (VSMCs) switch to the synthetic phenotype to proliferate and migrate. This is followed by return to the contractile phenotype in the later stages of CCG during collateral maturation. miR-145 plays an important role in the switch to the contractile phenotype. CCG is impaired in the metabolic syndrome, both in the human and in the rat model (JCR). We assessed the hypothesis that lack of CCG in the metabolic syndrome rat model is due to aberrant phenotypic modulation of VSMCs by miR-145-mediated mechanisms and that restoration of normal physiological miR-145 levels in the metabolic syndrome would improve CCG. CCG was stimulated by transient, repetitive LAD occlusion and evaluated after 9 days by measurements of coronary blood flow (microspheres). miR-145 was delivered to the myocardium of JCR rats via an adenoviral vector (miR-145-Adv). Smooth muscle (SM)-specific expression was achieved by inserting a SM-specific promoter, SM22a, into the vector directly in front of the miR sequence. We found that in the metabolic syndrome rat, miR-145 is decreased during the later stages of CCG (~3±0.2 fold on days 6 and 9 of CCG vs. SD, n=6). This correlated with decreased expression of SM-specific contractile proteins (~5.5±0.1 fold on day 6 and ~10±0.5 fold on day 9 LAD occlusion vs. SD, n=6) indicative of failure of VSMCs to return to the contractile phenotype in the later stages of CCG. This correlated with the failure of the JCR animals to develop collaterals. Delivery of miR-145 in the later stages of CCG (days 6-9) by adenoviral vector, at the level equivalent to that expressed by VSMCs in the normal rats (0.35±0.04 pg/200ng RNA JCR+miR-145-Adv vs. 0.30±0.02 pg/200ng mRNA SD, n=6), restored the contractile phenotype of JCR VSMCs and completely restored CCG in the metabolic syndrome (collateral zone/normal zone flow ratio was 0.16±0.02 JCR vs. 0.95±0.02 JCR+miR-145-Adv vs. 0.87±0.01 SD, n=6). We conclude that restoration of the VSMC contractile phenotype through miR-145 delivery is a highly promising therapeutic intervention for restoration of CCG in the metabolic syndrome.
- © 2012 by American Heart Association, Inc.