A novel cardioprotective agent in cardiac transplantation: Metformin activation of AMP-activated protein kinase decreases acute ischemia-reperfusion injury and chronic rejection

Jocelyn T. Chin, Joshua J. Troke, Naoyuki Kimura, Satoshi Itoh, Xi Wang, Owen P. Palmer, Robert C. Robbins, Michael P. Fischbein

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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 longterm 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 metforminand AMPK-mediated pathways to suppress acute I-R injury.

Original languageEnglish (US)
Pages (from-to)423-432
Number of pages10
JournalYale Journal of Biology and Medicine
Volume84
Issue number4
StatePublished - Dec 2011
Externally publishedYes

Keywords

  • Acute rejection
  • AMPK
  • Apoptosis
  • Cardiac transplantation
  • Chronic rejection
  • I-R injury
  • Metformin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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