Abstract 19375: Rapamycin Treatment Regulates miRNAs Associated With Mitochodrial and Endoplasmic Reticulum Functions in a Pig Model of Miocardial Ischemia-reperfusion Injury
Introduction: Previously(Lassaletta et al,PMC3943541)we showed that Rapamycin treatment of normal pigs subjected to an acute myocardial ischemia-reperfusion injury (IRI) was associated with increase myocardial necrosis and refractory left ventricle (LV) defibrillations. In an effort to better understand rapamycin effects we applied a non-bias genomic analysis to determine if microRNAs were modified by rapamycin treatment in this pre-clinical animal model of IRI.
Hypothesis: We hypothesized that microRNA expression were modified by rapamycin-treated and would identify novel and meaningful pharmacological mechanisms related to its detrimental effects on reperfusion injury.
Methods: Young male Yorkshire swine (16-19 kg) received either no drug (controls, n=5) or were given 4mg of oral rapamycin daily (n=5). After two weeks of treatment, all animals underwent median sternotomy and the mid-LAD was occluded for 60 minutes followed by 120 minutes of reperfusion. RNA was extracted from LV non-ischemic and ischemic areas from each group and processed (according to the manufacture′s specifications at Brown University Genomic Core facility) for microRNA (miRNA) expression analysis using a Affymetrix GeneChip miRNA3.0 Array containing over 25,000 probe sets of which 257 miRNA probes of domestic pigs. Data were processed using MetaCore version 5.0 (GeneGo, St Joseph, MI) for both statistical (FDR: p<0.05) and pathway analysis.
Results: miRNA regulated in 5 animals per group were annotated for human orthologs. A total of 23 miRNAs were differentially expressed. Interestingly, all miRNAs were down-regulated in the rapamycin-treated animals. Of those, nine had human orthologs: miR 181c-3p was highly represented followed by miR323a-5p, miR1245b-3p, miR4324, miR331-5p, miR491-5p and miR490-3p.
Conclusions: Recent studies show that miRNA 181c regulates myocardial mitochondrial function through cytochrome c oxidase and complex IV gene expressions (PMCID: PMC4014556)and regulates Glucose-regulated protein (GRP78)/BiP [an endoplasmic reticulum stress (ER) chaperone](PMID: 24696166). Hence It is likely that rapamycin effects (detrimental or not) are associated with mitochondrial function and ER stress response.
Author Disclosures: C. Bianchi: None. P.S. Oliveira: None. A.D. Lassaletta: None. F.W. Sellke: Consultant/Advisory Board; Modest; medicines company, advisory committee, boehringer ingleheim, DSMB. K.G. Franchini: None. C. Schorl: None.
- © 2015 by American Heart Association, Inc.