Abstract 17592: The Cardiolipin-targeting Peptide Bendavia Improves Post-ischemic Mitochondrial Energetics by Sustaining Native Respiratory Protein Complexes
Bendavia is a cell permeable, mitochondria-targeting peptide currently being tested in clinical trials for acute coronary syndromes, heart failure, and renal disease. In a series of studies, we have shown that Bendavia reduces cellular injury by targeting the mitochondrial inner membrane. In particular, Bendavia targets cardiolipin, a mitochondrial phospholipid that acts as “glue” to hold respiratory protein complex subunits together. In this study, we tested the hypothesis that Bendavia would improve post-ischemic mitochondrial function by sustaining native respiratory protein complexes. We utilized blue native gels (non-denaturing conditions) alongside high-resolution respirometry in permeabilized myocardial fibers to directly link changes in protein complexes to mitochondrial function. Rat hearts were subjected to ischemia-reperfusion (I/R) with or without 1nM Bendavia perfusion beginning at the onset of reperfusion. The native expression of mitochondrial Complexes III and V were significantly reduced after I/R, and were restored with Bendavia (see Figure). The appearance of degradation bands was also noted in hearts after I/R, and these products of protein complex breakdown were also significantly reduced with Bendavia treatment. Respirometry studies in permeabilized ventricular fibers showed lower Complex I-dependent respiration after I/R (208±19 v 42±9 pmol O2/mg*s) in control v I/R, respectively; P<0.05. Complex II-dependent respiration was also suppressed (753±41 v 168±13 pmol/mg*s in control versus I/R; P<0.05). Treatment with Bendavia led to significantly improved Complexes I- (100±13pmol O2/mg*s) and II-dependent (334±63pmol O2/mg*s) respiration (P<0.05 versus untreated IR for both). Taken together, these data indicate that Bendavia is protecting myocardium by preserving native mitochondrial respiratory complexes and sustaining mitochondrial function.
Author Disclosures: S.R. Shaikh: None. F. Moukdar: None. R.J. Alleman: None. D.S. Lark: None. P.D. Neufer: Consultant/Advisory Board; Modest; Stealth Peptides. D. Brown: Research Grant; Significant; Stealth Peptides. Consultant/Advisory Board; Significant; Stealth Peptides.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.