Abstract 12984: Long-term Therapy With Elamipretide Normalizes Protein Levels of the Signal Transducer and Activator of Transcription 3 (STAT3) in Mitochondria of Left Ventricular Myocardium of Dogs With Chronic Heart Failure

Abstract

Introduction: The signal transducer and activator of transcription 3 (STAT3) has recently been identified in mitochondria (MITO) of cardiomyocytes (mSTAT3). In STAT3-/- cells, the activities of MITO complexes I and II of the electron transport chain (ETC) were significantly reduced suggesting that mSTAT3 is required for optimal ETC function. In the heart, mSTAT3 activity is modulated by the heat shock protein H11 kinase (H11K) previously shown to be reduced in MITO of dogs with HF. We showed that long-term (3 months) therapy with elamipretide (ELA, Bendavia TM ), a novel MITO-targeting peptide, improves LV systolic function and to normalize MITO respiration, rate of ATP synthesis and H11K levels in MITO of LV cardiomyocytes of dogs with heart failure (HF). Hypothesis: This study tested the hypothesis that the level of mSTAT3 is reduced in LV myocardium of dogs with HF and that long-term therapy with ELA restores levels of mSTAT3. Methods: LV tissue was obtained from 14 dogs with microembolization-induced HF (LV ejection fraction ~30%) randomized to 3 months therapy with subcutaneous injections of ELA (0.5 mg/kg once daily, n=7) or saline (Control, n=7). LV tissue from 6 normal dogs was used for comparison. Protein levels of mSTAT3 and porin; the latter a MITO protein unchanged in HF (internal control), were determined in isolated MITO fractions from LV tissue using by Western blotting coupled with chemiluminescence. Protein band intensities were quantified in densitometric units (du). Results: Protein levels of porin was similar in all 3 study groups (NL:0.24±0.01; Control: 0.22±0.01; ELA: 0.23±0.01 du). Levels of mSTAT3 were 0.82±0.05 du in NL, decreased to 0.29±0.03 du in Controls (p<0.05 vs. NL) and were partially restored by ELA (0.53±0.05, p<0.05 vs. Control). Levels of mSTAT3 normalized to porin were 3.6±0.3 du in NL, decreased to 1.3±0.1 in Controls (p<0.05 vs. NL) and were restored to near normal levels following treatment with ELA (2.3±0.2, p<0.05 vs. Control). Conclusions: mSTAT3 level is reduced in MITO of from LV myocardium of HF dogs and restored after chronic therapy with ELA. Normalization of mSTAT3 by ELA likely contributed to the observed improvement in MITO function following therapy with ELA in dogs with chronic HF.