PMID- 28967097
OWN - NLM
STAT- MEDLINE
DCOM- 20180717
LR  - 20210109
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 174
IP  - 24
DP  - 2017 Dec
TI  - Chronic treatment with novel nanoformulated micelles of rapamycin, Rapatar, 
      protects diabetic heart against ischaemia/reperfusion injury.
PG  - 4771-4784
LID - 10.1111/bph.14059 [doi]
AB  - 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 3beta, 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.
CI  - (c) 2017 The British Pharmacological Society.
FAU - Samidurai, Arun
AU  - Samidurai A
AD  - Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, 
      Richmond, VA, USA.
FAU - Salloum, Fadi N
AU  - Salloum FN
AD  - Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, 
      Richmond, VA, USA.
FAU - Durrant, David
AU  - Durrant D
AD  - Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, 
      Richmond, VA, USA.
FAU - Chernova, Olga B
AU  - Chernova OB
AD  - Everon Biosciences, Inc., Buffalo, NY, USA.
FAU - Kukreja, Rakesh C
AU  - Kukreja RC
AD  - Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, 
      Richmond, VA, USA.
FAU - Das, Anindita
AU  - Das A
AUID- ORCID: 0000-0003-4422-7277
AD  - Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, 
      Richmond, VA, USA.
LA  - eng
GR  - R01 HL118808/HL/NHLBI NIH HHS/United States
GR  - R01 HL133167/HL/NHLBI NIH HHS/United States
GR  - R01 HL134366/HL/NHLBI NIH HHS/United States
GR  - R21 AG053654/AG/NIA NIH HHS/United States
PT  - Journal Article
DEP - 20171124
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Micelles)
RN  - 0 (Protective Agents)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Diabetes Mellitus, Experimental/drug therapy/*prevention & control
MH  - Diabetic Cardiomyopathies/drug therapy/*prevention & control
MH  - Male
MH  - Mice
MH  - Mice, Obese
MH  - Micelles
MH  - Myocardial Reperfusion Injury/drug therapy/*prevention & control
MH  - Nanostructures/*chemistry
MH  - Protective Agents/chemistry/*therapeutic use
MH  - Sirolimus/chemistry/*therapeutic use
PMC - PMC5727242
EDAT- 2017/10/03 06:00
MHDA- 2018/07/18 06:00
PMCR- 2018/12/01
CRDT- 2017/10/03 06:00
PHST- 2017/04/25 00:00 [received]
PHST- 2017/08/17 00:00 [revised]
PHST- 2017/09/13 00:00 [accepted]
PHST- 2017/10/03 06:00 [pubmed]
PHST- 2018/07/18 06:00 [medline]
PHST- 2017/10/03 06:00 [entrez]
PHST- 2018/12/01 00:00 [pmc-release]
AID - BPH14059 [pii]
AID - 10.1111/bph.14059 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2017 Dec;174(24):4771-4784. doi: 10.1111/bph.14059. Epub 2017 Nov 
      24.