Reduced Mitochondrial Aldehyde Dehydrogenase-2 Activity and Protein Levels in Left Ventricular Myocardium of Dogs with Heart Failure

Background: Heart failure (HF) promotes an increase in oxidative stress that leads to a build-up of reactive aldehydes such as 4-hydroxynonenal (4-HNE) that contribute to cardiomyocyte injury and death and to progressive global left ventricular (LV) dysfunction. Aldehyde dehydrogenases (ALDHs) are key enzymes that play a pivotal role in eliminating toxic aldehydes by catalyzing their oxidation to non-reactive acids. Mitochondrial ALDH2 plays a pivotal role in combating oxidative stress by reducing the cellular aldehyde load. This study examined protein levels of 4-HNE and ALDH2 as well as ALDH2 activity in LV myocardium of dogs with coronary microembolization-induced HF (LV ejection fraction ”30%). Methods: LV tissue from 7 HF dogs and from 6 normal (NL) dogs was used in the study. Using LV tissue extracts, 4-HNE-protein adducts levels were quantified using a commercially available Elisa kit and expressed as ng/mg protein. Protein levels of ALDH2 and porin, an internal loading control, were determined in isolated mitochondria by Western blotting coupled with Chemiluminescence. Band intensity were expressed in densitometric units (du). ALDH2 activity in isolated mitochondria was determined by measuring the conversion of propionaldehyde to propionic acid and the enzyme specifc activity was expressed as nmol NADH formed/min/mg protein. Results: Porin protein levels were unchanged in HF dogs compared to NL dogs (0.24 ± 0.01 vs. 0.26 ± 0.02 du, p\u3c0.05). 4-HNE protein adducts levels were significantly increased in HF dogs compared to NL dogs (399 ± 35 vs. 185 ± 21 du, p\u3c0.05); whereas ALDH2 protein levels were significantly decreased in HF dogs compared to NL dogs (0.49 ± 0.02 vs. 1.16±0.10du, p\u3c0.05). ALDH2 activity was significantly decreased in HF dogs compared to NL dogs (51 ±3 vs. 108 ±4 nmol NADH/min/mg, p\u3c0.05). Conclusions: In LV myocardium of dogs with chronic HF, ALDH2 protein levels and activity are decreased in the face of elevated burden of aldehydes (e.g. 4-HNE) paving the way for enhanced cellular injury, death and progressive LV dysfunction. Drugs that increase the activity of ALDH2 may be useful in the treatment of patients with chronic HF