Differential Regulation of mTOR Complexes with miR-302a Attenuates Myocardial Reperfusion Injury in Diabetes
Arun Samidurai,
Ramzi Ockaili,
Chad Cain,
Sean K. Roh,
Scott M. Filippone,
Donatas Kraskauskas,
Rakesh C. Kukreja,
Anindita Das
Affiliations
Arun Samidurai
Division of Cardiology, Pauley Heart Center, Box 980204, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Sanger Hall, Room 7020d & 7020b, Richmond, VA 23298-0204, USA
Ramzi Ockaili
Division of Cardiology, Pauley Heart Center, Box 980204, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Sanger Hall, Room 7020d & 7020b, Richmond, VA 23298-0204, USA
Chad Cain
Division of Cardiology, Pauley Heart Center, Box 980204, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Sanger Hall, Room 7020d & 7020b, Richmond, VA 23298-0204, USA
Sean K. Roh
Division of Cardiology, Pauley Heart Center, Box 980204, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Sanger Hall, Room 7020d & 7020b, Richmond, VA 23298-0204, USA
Scott M. Filippone
Division of Cardiology, Pauley Heart Center, Box 980204, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Sanger Hall, Room 7020d & 7020b, Richmond, VA 23298-0204, USA
Donatas Kraskauskas
Division of Cardiology, Pauley Heart Center, Box 980204, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Sanger Hall, Room 7020d & 7020b, Richmond, VA 23298-0204, USA
Rakesh C. Kukreja
Division of Cardiology, Pauley Heart Center, Box 980204, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Sanger Hall, Room 7020d & 7020b, Richmond, VA 23298-0204, USA; Corresponding author
Anindita Das
Division of Cardiology, Pauley Heart Center, Box 980204, Virginia Commonwealth University Medical Center, 1101 East Marshall Street, Sanger Hall, Room 7020d & 7020b, Richmond, VA 23298-0204, USA; Corresponding author
Summary: Persistent activation of mTOR (mammalian target of rapamycin) in diabetes increases the vulnerability of the heart to ischemia/reperfusion (I/R) injury. We show here that infusion of rapamycin (mTOR inhibitor) at reperfusion following ischemia reduced myocardial infarct size and apoptosis with restoration of cardiac function in type 1 diabetic rabbits. Likewise, treatment with rapamycin protected hyperglycemic human-pluripotent-stem-cells-derived cardiomyocytes (HG-hiPSC-CMs) following simulated ischemia (SI) and reoxygenation (RO). Phosphorylation of S6 (mTORC1 marker) was increased, whereas AKT phosphorylation (mTORC2 marker) and microRNA-302a were reduced with concomitant increase of its target, PTEN, following I/R injury in diabetic heart and HG-hiPSC-CMs. Rapamycin inhibited mTORC1 and PTEN, but augmented mTORC2 with restoration of miRNA-302a under diabetic conditions. Inhibition of miRNA-302a blocked mTORC2 and abolished rapamycin-induced protection against SI/RO injury in HG-hiPSC-CMs. We conclude that rapamycin attenuates reperfusion injury in diabetic heart through inhibition of PTEN and mTORC1 with restoration of miR-302a-mTORC2 signaling.
