Abstract 14054: Chronic Treatment With Novel Nanoformulated Micelles of Rapamycin, Rapatar, Protects Diabetic Heart Against Ischemia/reperfusion Injury
Background: Elevated mammalian target of rapamycin (mTOR) signaling contributes to the pathogenesis of diabetes and plays a critical role in myocardial ischemia/reperfusion (I/R) injury. Since the putative inhibitor of mTOR, rapamycin, has very poor water solubility and low absorption rate, its in vivo delivery and toxicity, especially during chronic treatment, may limit clinical utility. Rapatar are novel nanoformulated micelles of rapamycin (based on Pluronic block copolymers as nanocarriers) that have been rationally designed to increase water solubility of rapamycin in order to facilitate oral administration and enhance bioavailability. We therefore examined the effect of Rapatar in improving metabolic status and protection against I/R injury in type 2 diabetic (T2D) mice.
Methods and Results: Adult male db/db mice were treated daily for 10 weeks with Rapatar (0.75 mg/kg/day, p.o.). At the end of treatment, the hearts were subjected to global ischemia (30 min) and reperfusion (1 hr) in Langendorff mode. Rapatar reduced fasting plasma glucose levels (266±48 mg/dL vs 478±28 mg/dL, p<0.01, n=10) (Fig. A) without affecting of body weight as compared to control db/db mice. Rapatar also improved glucose tolerance and insulin sensitivity compared to control (Fig. B, C). Myocardial infarct size, measured by tetrazolium staining, was reduced in rapatar-treated mice (20.4±2.7 % vs controls 49.9±5.1 %, n=6, p<0.0005; Fig. D). Western blot analyses confirmed a significant inhibition in phosphorylation of ribosomal protein S6 (downstream target of mTORC1), but not AKT (Ser473, target of mTORC2) following chronic treatment with Rapatar (Fig. E).
Conclusion: Chronic Rapatar treatment improved metabolic status and reduced myocardial infarction following I/R injury in diabetic mice. Rapatar may be a potentially safe and novel therapeutic option for diabetes-induced cardiovascular complications.
Author Disclosures: A. Das: None. F.N. Salloum: None. D. Durrant: None. O. Chernova: None. R.C. Kukreja: None.
- © 2014 by American Heart Association, Inc.