057 - Long-Term Therapy with Elamipretide Reverses Abnormalities of Cardiolipin Synthesis and Remodeling in Left Ventricular Myocardium of Dogs with Chronic Heart Failure

Background: Mitochondrial (MITO) abnormalities and energy deprivation occur in heart failure (HF). Cardiolipin (CL) is the signature lipid of the MITO inner membrane, site of the electron transport chain (ETC). CL plays a key role in MITO biogenesis, fission and fusion dynamics, and respiration and, as such, is essential for MITO structural integrity and oxidative phosphorylation. Increased production of reactive oxygen species (ROS) by MITO occurs in HF and can trigger CL peroxidation, thus damaging the MITO inner membrane. We and others showed that HF is associated with abnormal MITO biogenesis, fission and fusion dynamics, and respiration resulting in a state of “energy deprivation”. Objective: This study examined the effects of long-term therapy with elamipretide (ELAM), a MITO-targeting peptide, on the level of 4-hydroxynonenal (4-HNE), a bi-product of lipid peroxidation, CL level, level of CL synthase (CLS), a key enzyme in the synthesis of CL and level Tafazzin-1 (TAZ1), an essential CL remodeling enzyme, in LV myocardium of dogs with coronary microembolization-induced chronic HF. Methods: Studies were performed in LV tissue from 14 HF dogs randomized to 3 months therapy with subcutaneous injections of ELAM (0 5 mg/kg once daily, 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 Level of 4-HNE was measured using an ELISA kit Total CL and (18:2)4CL species were measured using mass spectroscopy and were normalized to LV MITO protein levels. TAZ1 and CLS protein levels were measured by Western blotting and bands quantified in densitometric units (du). Results: Compared to NL, 4-HNE significantly increased in HF dogs while protein levels of CLS and TAZ1 decreased significantly (Table 1). These abnormalities were associated with decreased total CL and (18:2)4CL level (Table). Treatment with ELAM normalized levels of 4-HNE, CLS, TAZ1, total CL and (18:2)4CL (Table). Conclusion: In the failing LV myocardium CL peroxidation occurs and is associated with reduced levels of CL and levels of proteins that regulate CL synthesis and remodeling. Long-term therapy with ELAM prevents CL peroxidation and normalizes CL level and levels of proteins that regulate CL synthesis and remodeling. These results provide further support for the continued development of ELAM for the treatment of patients with HF.Table 1NLHF-ControlHF + ELAM4-HNE (ng/mg protein)185 ± 21399 ± 35*P < .05 vs. NL.252 ± 18†P < .05 vs. HF-Control.Total CL (nmol/mg MITO protein)11.0 ± 0.716.5 ± 0.5*P < .05 vs. NL.8.9 ± 0.70†P < .05 vs. HF-Control.(18:2)4 CL (nmol/mg MITO protein)8.5 ± 0.64.9 ± 0.48*P < .05 vs. NL.7.0 ± 0.05†P < .05 vs. HF-Control.CLS1 protein level (du)2.39 ± 0.160.93 ± 0.12*P < .05 vs. NL.1.64 ± 0.11†P < .05 vs. HF-Control.TAZ1 protein level (du)0.69 ± 0.040.36 ± 0.04*P < .05 vs. NL.0.58 ± 0.04†P < .05 vs. HF-Control.* P < .05 vs. NL.† P < .05 vs. HF-Control. Open table in a new tab