title: A novel cardioprotective agent in cardiac transplantation: metformin activation of AMP-activated protein kinase decreases acute ischemia-reperfusion injury and chronic rejection.
abstract: The main cause of mortality after the first year from cardiac transplantation is cardiac allograft vasculopathy (CAV), which leads to chronic rejection of the heart. To improve long-term outcomes in cardiac transplantation, treatments to prevent or diminish CAV are actively being researched. Ischemia-reperfusion (I-R) injury has been shown to be the strongest alloantigen-independent factor in the development of CAV. Here, we investigate the use of metformin in murine cardiac transplantation models as a novel cardioprotective agent to limit acute I-R injury and subsequent chronic rejection. We show that metformin treatment activates AMP-activated kinase (AMPK) in vitro and in vivo. In the acute transplantation model, metformin activation of AMPK resulted in significantly decreased apoptosis in cardiac allografts on postoperative day (POD) 1 and 8. In the chronic transplantation model, metformin pretreatment of allografts led to significantly improved graft function and significantly decreased CAV, as measured on POD 52. Taken together, our results in the acute and chronic rejection studies suggest a potential cardioprotective mechanism for metformin; we demonstrate a correlation between metformin-induced decrease in acute I-R injury and metformin-related decrease in chronic rejection. Thus, one of the ways by which metformin and AMPK activation may protect the transplanted heart from chronic rejection is by decreasing initial I-R injury inherent in donor organ preservation and implantation. Our findings suggest novel therapeutic strategies for minimizing chronic cardiac rejection via the use of metformin- and AMPK-mediated pathways to suppress acute I-R injury.
authors.affiliation: Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Jocelyn T
authors.initials: JT
authors.lastname: Chin
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Troke
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kimura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Itoh
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Owen P
authors.initials: OP
authors.lastname: Palmer
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
authors.forename: Michael P
authors.initials: MP
authors.lastname: Fischbein
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D006084:Graft Rejection / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016027:Heart Transplantation; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014184:Transplantation, Homologous
chemical_list: D002316:Cardiotonic Agents; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide