Abstract 12608: Bone Marrow Stromal Cell Derived Exosomes Carrying Microrna-486 Attenuate H/r-Induced Cardiac Myocyte Damage In Vitro and I/r-Induced Myocardial Injury In Vivo
We have reported that Toll-like receptor 4 deficiency (TLR4-/-) or the TLR2 ligand, Pam3CSK4, induces protection against myocardial ischemia/reperfusion (I/R) injury. We found that the levels of myocardial microRNA-486 (miR-486) in TLR4-/- mice or Pam3CSK4-treated mice were significantly greater than in control groups.We hypothesized that miR-486 protects cardiac myocytes from hypoxia/reoxygenation (H/R) induced damage in vitro and myocardial I/R injury in vivo. First, we treated mice with Pam3CSK4 in sham and I/R mice and examined microRNA-486 levels in serum exosomes. Second, we transfected bone marrow stromal cells (BMSCs) with miR-486 mimics and isolated exosomes carrying miR-486 (miR-486/exosomes) from BMSCs. We examined the effects of miR-486/exosomes on H/R-induced adult cardiac myocyte damage in vitro and on myocardial I/R injury in vivo. Pam3CSK4 treatment significantly increases the miR-486 levels in serum exosomes of sham and I/R mice (n=4/group) and in exosomes derived from BMSCs. Transfection of adult cardiac myocytes with miR-486/exosomes markedly suppressed PTEN expression, and increased Akt phosphorylation (n=3/group). Transfection of H9C2 cardiomyoblasts with lentivirus expressing miR-486 significantly attenuated H/R-induced LDH release, increased cell viability and prevented H/R-induced caspase-3/7 and caspase-8 activities (n=6/group). Transfection of the myocardium with miR-486/exosomes immediately before the hearts were subjected to ischemia (45 min) followed by reperfusion (4 h) significantly reduced infarct size by 58% compared with the I/R control group (n=6/group). Scrambled miR/exosomes did not affect I/R-induced myocardial infarction (n=6). Transfection of miR-486, in FDA-approved nanoparticles, significantly improved cardiac function at 3 and 7 days after reperfusion (n=6). Western blot showed that transfection with miR-486/exosomes suppressed PTEN expression and increased Akt phosphorylation in the myocardium compared with I/R control (n=4/group). We conclude that miR-486 protects against H/R-induced cell damage and myocardial I/R injury via activation of PI3K/Akt signaling by targeting PTEN. Exosomes may be an attractive vehicle for carrying miRs in clinical application.
Author Disclosures: X. Wang: None. T. Ha: None. X. Zhang: None. C. Lu: None. L. Liu: None. R. Kao: None. J. Kalbfleisch: None. D. Williams: None. C. Li: None.
- © 2014 by American Heart Association, Inc.