Abstract 12882: Monotherapy With Bendavia (MTP-131), a Novel Mitochondria-Targeting Peptide, Normalizes H11 Kinase Protein Levels in Nuclear and Mitochondrial Fractions of Left Ventricular Myocardium of Dogs With Advanced Heart Failure
Introduction: The heat shock protein H11 kinase (H11K) is expressed in the heart and rapidly increases in response to increased cardiac workload. Deletion of H11K accelerates LV dysfunction and remodeling by deactivating STAT3, a stress-inducible transcription factor. Deactivation of STAT3 has been shown to adversely impact mitochondrial function. We previously showed that chronic therapy (3 months) with Bendavia (BEN, MTP-131), a novel mitochondria-targeting peptide, improves LV function in dogs with heart failure (HF) and normalizes mitochondrial respiration and rate of ATP synthesis.
Hypothesis: This study tested the hypothesis that H11K protein level is reduced in mitochondrial (MF) and nuclear fractions (NF) of the failing LV and normalized after therapy with BEN.
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 (HF-Control, n=6). LV tissue from 6 normal dogs was used for comparison. LV tissue was used to extract MF and NF using commercially available isolation kits. Protein levels of H11K as well as Porin and Emerin, mitochondrial and nuclear proteins respectively not altered in HF, were determined by Western blotting and bands quantified in densitometric units (du).
Results: Results are shown in the table. Protein levels of Porin and Emerin were similar among the 3 study groups. Compared to NL, H11K protein level in MF and NF was significantly reduced in HF-controls. Therapy with BEN in HF-treated dogs (HF+BEN) significantly increased H11K protein level in both MF and NF to near normal.
Conclusions: H11K protein levels are reduced in MF and NF of LV in dogs with HF but normalized after chronic therapy with BEN. Restoring H11K with BEN likely contributed to the observed improvement in mitochondrial function and overall global LV function previously reported in dogs with advanced HF treated with BEN.
Author Disclosures: R.C. Gupta: None. K. Szekely: None. M. Wang: None. K. Zhang: None. V. Singh-Gupta: None. H.N. Sabbah: Research Grant; Significant; Stealth peptides, Inc.. Consultant/Advisory Board; Modest; Stealth Peptides, Inc..
- © 2014 by American Heart Association, Inc.