Abstract 19919: Cardioprotection During Early Reperfusion via Complex I Inhibition by Metformin
Introduction: Mitochondria (MITO) mediate cardiac injury during ischemia (ISC)-reperfusion (REP). Transient, reversible blockade of the proximal electron transport chain (ETC) during early REP limits cardiac injury. Classic ETC blockers have limited clinical potential. We studied the role for high dose metformin (MET) to reversibly inhibit complex I and protect at the MITO, cell and intact heart levels.
Hypothesis: MET therapy to acutely modulate MITO-driven injury can then be combined with prolonged protection via activation of AMPK signaling.
Methods: MITO were isolated from C57BLbl/6 hearts at baseline or following 25 min. ISC. H9c2 cells underwent chemical hypoxia (2 mM KCN) or control for 24 hr., with or without MET (1 mM) treatment. MET protection at REP was studied in isolated hearts using 25 min ISC and 60 min REP with or without 2 mM MET for initial 5 min REP. MET (to achieve 2 mM in plasma volume) was given IV at onset REP in C57BLbl/6 mice following 45 min LAD occlusion followed by 24 hr. REP.
Results: MET (2 mM) inhibition of complex I was 25±4%, n=5; p<0.05) in MITO following 25 min ISC. MET decreased total cell death in H9c2 from chemical hypoxia (either necrosis or apoptosis) measured by flow cytometry using propidium iodide-annexin V (20±2 vs. 28±4%, ±SE, n=5; p<0.05). Transient treatment with high dose (2 mM) MET reduced infarct size following ISC-REP in vitro (37±4 vs. 15±3, ±SE; n=5-6 each group, p<0.01) and more importantly following regional ISC-REP in vivo (20±2 vs. 8±3% area at risk; ±SE, n=5-6, p<0.05). MET at 2 mM in vivo was safe and tolerated in vivo, with 100% survival at 24 hrs. (n=6) without hypoglycemia (n=6)..
Conclusion: Acute high dose MET therapy inhibited complex I, with selectively greater inhibition in ISC-damaged MITO. Acute complex I inhibition at onset of REP by MET reduced infarct size in vitro and in vivo, in line with previous results with transient, acute ETC blockade complex I inhibition during early REP using other agents. MET, even with transient high dose, is safe. Acute treatment can be combined with continued chronic therapy that activates canonical AMPK signaling pathways during later REP to consolidate the protection achieved by acute high dose therapy during early REP.
Author Disclosures: A. Mohsin: None. Q. Chen: None. N. Quan: None. M. Maceyka: None. A. Samidurai: None. J. Thompson: None. Y. Hu: None. J. Li: None. E.J. Lesnefsky: None.
- © 2016 by American Heart Association, Inc.