Abstract 12903: Bendavia (MTP-131), a Mitochondria Targeting Peptide, Normalizes Dysregulation of Mitochondria Fission and Fusion Proteins in Myocardium of Dogs With Chronic Heart Failure

Introduction: Studies of mitochondria (MITO) ultrastructure in heart failure (HF) reveal considerable structural abnormalities along with marked hyperplasia and reduced organelle size. MITO are highly dynamic organelles whose morphology, distribution and activity is regulated by fission and fusion proteins that are also dysregulated in HF. We previously showed that chronic therapy with Bendavia (BEN, MTP-131), a novel mitochondria-targeting peptide, improves LV function in dogs with HF and normalizes MITO respiration and rate of ATP synthesis. Hypothesis: This study tested the hypothesis that chronic therapy with BEN in dogs with HF can reverse the dysregulation of MITO fission proteins (Fission-1, Fis1 and Dynamin-Related Protein-1, Drp1) and fusion proteins (Mitofusin-2, Mfn2 and Dominant Optic Atrophy-1, OPA1) in LV myocardium. Methods: 14 HF dogs were randomized to 3 months therapy with subcutaneous injections of BEN (0.5 mg/kg once daily, HF+BEN, n=7) or saline (HF-Control, n=7). LV tissue was obtained from all dogs at end of therapy and from 6 normal (NL) dogs for comparison. Protein level of Fis1 and Drp1 and of Mfn2 and OPA1 was measured with specific antibodies using Western blotting. In addition Porin, a MITO protein that is unaltered in HF, was also measured as internal control and all bands were quantified in densitometric units (du). Results: Results are shown in the table. Porin level was unchanged among the 3 study groups. Compared to NL, levels of Mfn2 and OPA1 were significantly reduced, and levels of Fis1 and Drp1 were significantly increased in HF-Controls. BEN restored protein levels of OPA1, Mfn2, Fis1, and Drp1 to near normal. Conclusions: Long-term therapy with BEN reversed the dysregulation of MITO fission and fusion proteins in LV myocardium of dogs with HF. These findings support the observations of improved MITO respiration and rate of ATP synthesis and the improved LV function seen in dogs with HF after chronic treatment with BEN.