Treatment of cardiomyocytes isolated from left ventricular myocardium of dogs with chronic heart failure with ALDA-1, an activator of aldehyde dehydrogenase-2, improves mitochondrial function

Abstract

Abstract Background Reactive oxygen species (ROS) generated by dysfunctional mitochondria (MITO) of the failing heart plays an important role in lipid peroxidation of polyunsaturated fatty acids in cell and MITO membranes resulting in the production of aldehydes, such as 4-hydroxy-2-nonenal (4-HNE). MITO aldehyde dehydrogenase-2 (mALDH2) is a key enzyme for the detoxification of endogenous aldehyde substrates through NAD dependent oxidation. ALDH2 catalyzes toxic 4HNE to nontoxic 4HNA in cardiac cells. We previously showed that mALDH2 expression and activity are markedly reduced in MITO of failing LV cardiomyocytes (CM), a maladaptation that can lead to considerable accumulation of 4-HNE in MITO and ultimately to progressive LV systolic and diastolic dysfunction. In this study, we tested the hypothesis that exposure of failing cardiomyocytes to ALDA-1, an activator of mALDH2, improves MITO function. Methods Freshly isolated CM from LV myocardium of dogs (n = 7) with heart failure (HF, LV ejection fraction ≤35%) and of normal (NL) dogs (n = 4) were incubated for 1 hour in absence (baseline) and presence of Alda-1 at concentration of 10 µM. After incubation, ADP-stimulated respiration (ADPresp) and maximal rate of ATP synthesis (ATPmax) were measured using Strathklein respirometer and bioluminescence ATP assay kit. Results Treatment of isolated CM from HF dogs with 10 µM Alda-1 significantly increased ADPresp (277 ± 18 vs. 189 ± 12 nAtom O/min/mg, p<0.05) and ATPmax (30 ± 3 vs. 16 ± 3 nmoles/min/mg, p<0.05) compared to untreated CM of HF dogs. Treatment of CM from NL dogs with 10 µM Alda-1 had no effect on ADPresp (488 ± 18 vs. 484 ± 19 nAtom O/min/mg) or ATPmax (54 ± 3 vs. 52 ± 2 nmoles/min/mg) compared to untreated NL CM. Conclusions Treatment of CM from HF dogs with Alda-1 improved overall MITO function. Activation of mALDH2 represents a potential viable therapeutic target for treating HF.