Shaikh 2014 Circulation

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.

Link: abstract

Shaikh SR, Moukdar F, Alleman RJ, Lark DS, Neufer PD, Brown D (2014)

Event:

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.

• Keywords: Acute coronary syndromes, Ischemia reperfusion, Mitochondria, Reperfusion injury, Pharmacology

• O2k-Network Lab: US NC Greenville Neufer PD, US NC Greenville Brown DA, US VA Blacksburg Brown DA

Labels: MiParea: Respiration, Pharmacology;toxicology 

Stress:Ischemia-reperfusion  Organism: Rat  Tissue;cell: Heart  Preparation: Permeabilized tissue 

Pathway: N, S  HRR: Oxygraph-2k 

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