Author + information
Mitochondria (MITO) of failed human hearts and hearts of dogs with experimental heart failure (HF) manifest abnormalities characterized by reduced state-3 respiration, reduced membrane potential (Δψm) and increased opening of membrane permeability transition pores (mPTP). These abnormalities lead to reduced ATP synthesis that adversely impacts LV function. We tested the hypothesis that chronic therapy with Bendavia (MTP-131), a novel mitochondria-targeting peptide shown to increase LV systolic function in HF dogs, reverses these MITO abnormalities.
Cardiomyocytes isolated from LV of 12 HF dogs produced by coronary microembolizations (LV ejection fraction ∼30%) were used. Dogs were randomized to 3 months therapy with subcutaneous injections of Bendavia (0.5 mg/kg once daily, n=7) or saline (Control, n=7). MITO state-3 respiration was measured using a Clark electrode. Δψm was measured using the dye JC-1 and mPTP was measured based on the rate of calcein exit from MITO. ATP was measured using the bioluminescent ApoSENSORTM assay kit.
Compared to Control, Bendavia significantly improved MITO state-3 respiration, increased Δψm, decreased the rate of calcein exit from MITO thus decreasing mPTP opening and increased in ATP synthesis (Table).
Therapy with Bendavia reverses abnormalities of MITO function in LV of dogs with HF and increases ATP synthesis. The latter can explain the observed improvement of LV systolic function following therapy with Bendavia.
|MITO State-3 Respiration (ng atoms of oxygen consumed/mg protein/min)||150 ± 39||322±50*|
|Δψm (ratio of red/green fluorescence)||0.36 ± 0.03||0.77 ± 0.10*|
|Calcein Fluorescence (% of maximum)||54.3 ± 3.5||66.0 ± 4.8*|
|ATP Synthesis (RLU/μg protein)||447 ± 85||856 ± 64*|
↵* =p<0.05 vs. Control; RLU = relative light units. ATP = adenosine triphosphate.
Poster Sessions, Expo North
Sunday, March 10, 2013, 9:45 a.m.-10:30 a.m.
Session Title: Heart Failure: Pharmacologic Therapy
Abstract Category: 17. Heart Failure: Therapy
Presentation Number: 1223-310
- 2013 American College of Cardiology Foundation