Abstract 85: Long-term Monotherapy with Bendavia (MTP-131), A Novel Mitochondria-Targeting Peptide, Restores H11 Kinase Protein Levels in Mitochondrial Fractions of Left Ventricular Myocardium of Dogs with Advanced Heart Failure

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Abstract

Background: The heat shock protein H11 kinase (H11K) is expressed in the heart of dogs, rodents and humans and rapidly increases in response to increased contractile workload. Deletion of H11K in pressure overload transgenic mice accelerates LV dysfunction and remodeling by deactivating STAT3, a stress-inducible transcription factor. Deactivation of STAT3 has been shown to adversely impact mitochondrial respiration and consequently oxidative phosphorylation. We previously showed that chronic therapy (3 months) with Bendavia (BEN, MTP-131), a novel mitochondria-targeting peptide, improves LV systolic function in dogs with heart failure (HF) and normalizes mitochondrial respiration and rate of ATP synthesis in LV myocardium of dogs with HF. This study tested the hypothesis that H11K is reduced in mitochondria of the failing heart and that long-term therapy with BEN normalizes levels of this key heat shock protein.

Methods: LV tissue was obtained from 12 dogs with microembolization-induced HF (LV ejection fraction ~30%) randomized to 3 months therapy with subcutaneous injections of BEN (0.5 mg/kg once daily, n=6) or saline (Control, n=6). LV tissue from 6 normal dogs was used for comparison. Tissue samples were used to extract mitochondrial fractions (MF). Protein levels of H11K and Porin, a mitochondrial protein not altered in HF, were determined in MF by Western blotting and protein band were quantified in densitometric units (du).

Results: Protein level of Porin in MF was similar among NL, Control and BEN-treated dogs (0.24±0.0 vs. 0.22±0.01 vs. 0.23±0.01 du, respectively). Level of H11K was 0.45±0.03 du in NL, decreased to 0.17±0.02 in Controls (p<0.05vs. NL) and was normalized by BEN (0.37±0.05, p<0.05 vs. Control). H11K normalized to Porin was 1.93±0.23 du in MF of NL dogs, decreased to 0.78±0.0.09 du in Controls (p<0.05 vs. NL) and was restored to near normal levels after treatment with BEN (1.61±0.20 du, p<0.05 vs. Control).

Conclusions: H11K protein levels are reduced in MF from LV myocardium of dogs with HF and normalized after chronic therapy with BEN. Restoring H11K with BEN likely contributed to the observed improvement in mitochondrial respiration and rate of ATP synthesis previously reported after long-term therapy with BEN.

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