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

doi:10.1016/j.isci.2020.101863

Differential Regulation of mTOR Complexes with miR-302a Attenuates Myocardial Reperfusion Injury in Diabetes

iScience. 2020 Nov 26;23(12):101863. doi: 10.1016/j.isci.2020.101863. eCollection 2020 Dec 18.

Authors

Arun Samidurai¹, Ramzi Ockaili¹, Chad Cain¹, Sean K Roh¹, Scott M Filippone¹, Donatas Kraskauskas¹, Rakesh C Kukreja¹, Anindita Das¹

Affiliation

¹ 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.

Abstract

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.

Keywords: Human Metabolism; Molecular Biology.