Shaikh 2014 Circulation: Difference between revisions
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Revision as of 09:14, 16 June 2015
Shaikh SR, Moukdar F, Alleman RJ, Lark DS, Neufer PD, Brown D (2014) The cardiolipin-targeting peptide Bendavia improves post-ischemic mitochondrial energetics by sustaining native respiratory protein complexes. Am Heart Assoc 130:A17592. |
ยป abstract
Shaikh SR, Moukdar F, Alleman RJ, Lark DS, Neufer PD, Brown D (2014) Am Heart Assoc
Abstract: 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 โglueโ 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 (208ยฑ19 v 42ยฑ9 pmol O2/mg*s) in control v I/R, respectively; p<0.05. Complex II-dependent respiration was also suppressed (753ยฑ41 v 168ยฑ13 pmol/mg*s in control versus I/R; p<0.05). Treatment with Bendavia led to significantly improved Complexes I- (100ยฑ13pmol O2/mg*s) and II-dependent (334ยฑ63pmol 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. โข Keywords: Acute coronary syndromes, Ischemia reperfusion, Mitochondria, Reperfusion injury, Pharmacology
โข O2k-Network Lab: US NC Greenville Neufer PD, US NC Greenville Brown DA
Labels: MiParea: Respiration
Stress:Ischemia-reperfusion Organism: Rat Tissue;cell: Heart Preparation: Permeabilized tissue
HRR: Oxygraph-2k
Labels