Abstract 17991: The Cardiolipin-targeting Peptide Bendavia Protects Post-ischemic Myocardium by Preserving Mitochondrial Membrane Fluidity
Bendavia is a mitochondria-targeting peptide currently being tested in the EMBRACE-STEMI trial for reducing injury during acute coronary syndromes. Across pre-clinical models, Bendavia preserves mitochondrial function by targeting the mitochondrial phospholipid cardiolipin, but it is not understood how targeting cardiolipin ultimately leads to cardioprotection. Membrane fluidity, which regulates the assembly of mitochondrial proteins, is directly influenced by cardiolipin levels/content. We recently observed augmented fluidity with Bendavia in cardiolipin-enriched lipid vesicles, but the pathophysiological relevance has not been established. We hypothesized that mitochondrial membrane fluidity would be decreased after cardiac reperfusion, and that targeting cardiolipin with Bendavia protects tissue by sustaining mitochondrial membrane fluidity. Following ex vivo ischemia-reperfusion, rat left ventricular mitochondria were isolated and mitochondrial membrane fluidity was assessed. We utilized two different probes to comprehensively assess mitochondrial membrane fluidity: one that detects acyl side fluidity (DPH polarization; n=6-15 per group), and another that reports on phospholipid headgroup fluidity (MC540 fluorescence (AU); n=3-4 per group). Mitochondrial acyl side chain fluidity decreased after cardiac ischemia-reperfusion (DPH polarization increased 74±16% from control). Phospholipid headgroup fluidity was also decreased following ischemia-reperfusion (mean fluorescence was 535,371 versus 940,139 AU in control). Post-ischemic Bendavia administration improved mitochondrial membrane fluidity in both acyl side chains (mean polarization was increased by only 4% compared to non-ischemic mitochondria) and phospholipid headgroups (mean MC540 fluorescence significantly increased to 804,109 AU). Upcoming studies will determine if improved supercomplex-dependent reparation is a direct consequence of sustaining mitochondrial membrane fluidity. In conclusion, these studies are the first to show clear declines in mitochondrial fluidity during acute coronary syndromes, and highlight the promise of therapies that improve cardiolipin-dependent fluidity.
- © 2013 by American Heart Association, Inc.