Abstract 13960: Improved Mitochondrial Respiration in Left Ventricular Myocardium of Dogs with Heart Failure Following Long-term Therapy with Bendavia (MTP-131) is Associated with Suppression of the Pro-inflammatory State and Down-regulation of Inducible Nitric Oxide Synthase
Introduction: An inflammatory state exists in heart failure (HF) evidenced by elevated cytokines including tumor necrosis factor- α (TNFα), interlukin-6 (IL-6) and c-reactive protein (CRP). Inflammation triggers increased expression of inducible nitric oxide (NO) synthase (iNOS). NO generated by iNOS can inhibit activity of cytochrome c oxidase (COX-IV, complex-IV) in mitochondria (MITO) and suppress respiration leading to reduced ATP synthesis and worsening LV function. We previously showed that Bendavia (BEN, MTP-131), a MITO-targeting peptide, improves LV function and MITO rate of ATP synthesis in dogs with HF.
Hypothesis: Long-term therapy with BEN in dogs with HF suppresses the inflammatory state, normalizes levels of iNOS and improves MITO respiration.
Methods: 14 microembolization-induced HF dogs were randomized to 3 months therapy with subcutaneous injections of BEN (0.5 mg/kg once daily, n=7) or saline (HF-Control, n=7). LV tissue and plasma were obtained at end of study from all dogs and from 6 normal (NL) dogs for comparison. MITO state-3 respiration (ng atoms of Oxygen consumed/mg/min) was measured using a Strathkelvin respirometer and protein level of iNOS was measured by Western blotting and quantified in densitometric units (du). COX-IV activity was measured polarographically and expressed as nmols of oxygen/min/mg. Plasma levels of TNFα, IL-6 and CRP was measured by ELISA.
Results: Compared to NL, HF-Controls showed reduced state-3 respiration and COX-IV activity and increased iNOS and plasma levels of TNFα, IL-6 and CRP (Table). Treatment with BEN normalized state-3 respiration, COX-IV activity and levels of iNOS and reduced plasma levels of TNFα, IL-6 and CRP.
Conclusions: Long-term therapy with BEN suppresses inflammation, down-regulates iNOS and restores normal MITO COX-IV activity and respiration in dogs with HF. Normalization of this signaling pathway likely contributed to improved LV function seen in HF dogs treated with BEN.
Author Disclosures: H.N. Sabbah: Research Grant; Significant; Stealth Peptides, Inc.. Consultant/Advisory Board; Modest; Stealth Peptides, Inc.. R.C. Gupta: None.
- © 2014 by American Heart Association, Inc.