Abstract 11878: Bendavia, a Novel Mitochondria Targeting Peptide, Improves Mitochondrial Function in Circulating Blood Monocytes From Dogs With Chronic Heart Failure

Abstract

Introduction: We previously showed that mitochondrial (MITO) function of the failing heart is abnormal as evidenced by reduced MITO respiration and reduced MITO ATP synthesis. We also showed that this abnormality extends to MITO of circulating blood monocytes (MCs). Therapy with Bendavia, a novel MITO targeting peptide, has been shown to normalize MITO function of failing cardiomyocytes. Hypothesis: Bendavia will also normalize abnormalities of MITO function of MCs of dogs with chronic heart failure (HF). Methods: Peripheral blood samples were obtained from 6 normal (NL) dogs and 6 dogs with coronary microembolizations-induced HF (LV ejection fraction ~30%) and used to isolate MCs by sequential Ficoll and Percoll density gradients. An XFe/XF96 analyzer (Seahorse Bioscience) was used to measure oxygen consumption rates (OCR) in MCs in the presence and absence of 1 μM oligomycin, 0.5 μM FCCP, or 1 μM each rotenone and antimycin. MITO proton leak, maximal respiration (MAXresp), and spare respiratory capacity (SRC) were measure in the presence and absence of 0.1, 1.0 and 10 μM concentrations of Bendavia and results expressed in pmols OCR/min/μg protein. Results: Proton leak, MAXresp and SRC were abnormal in MCs of HF dogs compared to NL dogs. Incubation with Bendavia had no effect on any of the measures of MCs MITO function of NL dogs (Table). In contrast, MITO function of MCs from HF dogs was nearly normalized after treatment with Bendavia (Table). Conclusions: MITO function is abnormal in circulating blood MCs of dogs with HF. Bendavia had no effect on MITO function of MCs from NL dogs. Treatment with Bendavia of MCs from HF dogs elicited a dose-dependent correction/normalization of MITO function. These findings support the use of circulating blood MCs as means of assessing MITO dysfunction in HF and as a marker of potential benefits derived from treatment with MITO targeted therapies.