title: Reperfusion Therapy with Rapamycin Attenuates Myocardial Infarction through Activation of AKT and ERK.
abstract: Prompt coronary reperfusion is the gold standard for minimizing injury following acute myocardial infarction. Rapamycin, mammalian target of Rapamycin (mTOR) inhibitor, exerts preconditioning-like cardioprotective effects against ischemia/reperfusion (I/R) injury. We hypothesized that Rapamycin, given at the onset of reperfusion, reduces myocardial infarct size through modulation of mTOR complexes. Adult C57 male mice were subjected to 30 min of myocardial ischemia followed by reperfusion for 1 hour/24 hours. Rapamycin (0.25 mg/kg) or DMSO (7.5%) was injected intracardially at the onset of reperfusion. Post-I/R survival (87%) and cardiac function (fractional shortening, FS: 28.63 ± 3.01%) were improved in Rapamycin-treated mice compared to DMSO (survival: 63%, FS: 17.4 ± 2.6%). Rapamycin caused significant reduction in myocardial infarct size (IS: 26.2 ± 2.2%) and apoptosis (2.87 ± 0.64%) as compared to DMSO-treated mice (IS: 47.0 ± 2.3%; apoptosis: 7.39 ± 0.81%). Rapamycin induced phosphorylation of AKT S473 (target of mTORC2) but abolished ribosomal protein S6 phosphorylation (target of mTORC1) after I/R. Rapamycin induced phosphorylation of ERK1/2 but inhibited p38 phosphorylation. Infarct-limiting effect of Rapamycin was abolished with ERK inhibitor, PD98059. Rapamycin also attenuated Bax and increased Bcl-2/Bax ratio. These results suggest that reperfusion therapy with Rapamycin protects the heart against I/R injury by selective activation of mTORC2 and ERK with concurrent inhibition of mTORC1 and p38.
authors.affiliation: Pauley Heart Center, Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Filippone
authors.affiliation: Pauley Heart Center, Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Samidurai
authors.affiliation: Pauley Heart Center, Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Sean K
authors.initials: SK
authors.lastname: Roh
authors.affiliation: Pauley Heart Center, Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Chad K
authors.initials: CK
authors.lastname: Cain
authors.affiliation: Pauley Heart Center, Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: He
authors.affiliation: Pauley Heart Center, Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
authors.affiliation: Pauley Heart Center, Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Kukreja
authors.affiliation: Pauley Heart Center, Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Anindita
authors.identifier: 0000-0003-4422-7277
authors.initials: A
authors.lastname: Das
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D015227:Lipid Peroxidation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors
chemical_list: D007166:Immunosuppressive Agents; D051028:bcl-2-Associated X Protein; D051058:Oncogene Protein v-akt; D020123:Sirolimus