Abstract 12949: Elamipretide (BendaviaTM) Restores 4-Hydroxy-2-Nonenal Protein Adducts and Aldehyde Dehydrogenase-2 Activity and mRNA Expression in Left Ventricular Myocardium of Dogs With Advanced Heart Failure
Background: 4-hydroxy-2-nonenal (4HNE), a reactive aldehyde, is generated in the failing heart and contributes to cardiomyocyte injury and death. Aldehyde dehydrogenase-2 (ALDH2) plays a key role in detoxifying mitochondrial (MITO) reactive aldehydes. We showed that chronic therapy with elamipretide (ELA), a novel MITO targeting peptide, improves LV systolic function, normalizes MITO function and reduces the burden of reactive oxygen species (ROS) in LV of dogs with microembolization-induced heart failure (HF).
Hypothesis: This study tested the hypothesis that chronic therapy with ELA normalizes protein levels of 4-HNE-adducts and ALDH2 activity and expression in LV myocardium of HF dogs (LV ejection fraction ~30%).
Methods: LV tissue from 14 HF dogs randomized to 3 months therapy with subcutaneous injections of ELA (0.5 mg/kg once daily, n=7) or subcutaneous injections of saline (control, CTR, n=7) and tissue from 6 normal (NL) dogs was used in the study. Level of 4-HNE-protein adducts was quantified using an Elisa kit. ALDH2 activity was assayed spectrophotometrically in LV MITO fractions by monitoring NADH formation from NAD to NADH at 340 nm. Protein levels of ALDH2 and porin (an internal loading control) were determined by Western blotting and band intensity quantified in densitometric units (du). mRNA expression of ALDH2 and GAPDH was measured in using real-time PCR.
Results: Data are shown in the table. Levels of 4HNE-protein adducts were significantly increased and ALDH2 activity, mRNA expression and protein levels significantly decreased in CTR compared to NL dogs. ELA normalized 4-HNE levels, ALDH2 activity and expression. There were no differences in the level of porin or GAPDH among the 3 study groups.
Conclusions: Chronic therapy with ELA normalizes ALDH2 and 4-HNE levels in LV myocardium of HF dogs. By limiting myocardial ROS burden, ELA contributes to cardiac end-organ protection and hence, to overall improvement in global LV function.
Author Disclosures: R.C. Gupta: None. V. Singh-Gupta: None. K. Zhang: None. J. Xu: None. H.N. Sabbah: None.
- © 2016 by American Heart Association, Inc.