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Chronic treatment with novel nanoformulated micelles of rapamycin, Rapatar, protects diabetic heart against ischaemia/reperfusion injury
Author(s) -
Samidurai Arun,
Salloum Fadi N,
Durrant David,
Chernova Olga B,
Kukreja Rakesh C,
Das Anindita
Publication year - 2017
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14059
Subject(s) - mtorc1 , pi3k/akt/mtor pathway , medicine , ampk , pharmacology , protein kinase b , reperfusion injury , endocrinology , ischemia , cardiac function curve , phosphorylation , chemistry , protein kinase a , signal transduction , heart failure , biochemistry
Background and Purpose Enhanced mammalian target of rapamycin (mTOR) signalling contributes to the pathogenesis of diabetes and plays a critical role in myocardial ischaemia/reperfusion (I/R) injury. Rapatar is a novel nanoformulated micellar of rapamycin, a putative inhibitor of mTOR that has been rationally designed to increase water solubility of rapamycin to facilitate p.o. administration and enhance bioavailability. We examined the effect of Rapatar on the metabolic status and protection against myocardial I/R injury in type 2 diabetic mice. Experimental Approach Adult male db/db mice were treated daily for 10 weeks with Rapatar (0.75 mg·kg −1 ·day −1 , p.o.) or vehicle. Isolated hearts were connected to a Langendorff perfusion system and subjected to global ischaemia (30 min) and reperfusion (1 h). Key Results Rapatar reduced fasting plasma glucose and triglyceride levels, prevented the gain in body weight and also improved glucose tolerance and insulin sensitivity in db/db mice compared with control. Cardiac function was improved following Rapatar treatment in db/db mice. Myocardial infarct size was reduced in Rapatar‐treated mice with improved post‐ischaemic rate–force product. Western blot analyses demonstrated a significant inhibition of phosphorylation of ribosomal protein S6 (downstream target of mTORC1), but not Akt (Ser 473 , target of mTORC2) following chronic treatment with Rapatar. Rapatar also induced phosphorylation of AMPK, STAT3, ERK1/2 and glycogen synthase kinase 3β, without interfering with phosphorylation of p38. Conclusion and implications Our studies indicate that chronic treatment with Rapatar improves metabolic status and cardiac function with a reduction of infarct size following myocardial I/R injury in diabetic mice.