Abstract
Aldehyde dehydrogenase (ALDH) gene superfamily consists of 19 isozymes. They are present in various organs and involved in metabolizing aldehydes that are biologically generated. For instance, ALDH2, a cardiac mitochondrial ALDH isozyme, is known to detoxify 4-hydroxy-2-nonenal, a reactive aldehyde produced upon lipid peroxidation in diabetic conditions. We hypothesized that inhibition of ALDH leads to the accumulation of unmetabolized 4HNE and consequently exacerbates injury in cells subjected to high glucose stress. H9C2 cardiomyocyte cell lines were pretreated with 10 μM disulfiram (DSF), an inhibitor of ALDH2 or vehicle (DMSO) for 2 hours, and then subjected to high glucose stress {33 mM D-glucose (HG) or 33 mM D-mannitol as an osmotic control (Ctrl)} for 24 hrs. The decrease in ALDH2 activity with DSF pretreatment was higher in HG group when compared to Ctrl group. Increased 4HNE adduct formation with DSF pretreatment was higher in HG group compared to Ctrl group. Pretreatment with DSF leads to potentiated HG-induced cell death in cultured H9C2 cardiomyocytes by lowering mitochondrial membrane potential. Our results indicate that ALDH2 activity is important in preventing high glucose induced cellular dysfunction.
Highlights
Aldehyde dehydrogenase (ALDH) is a family of multiple homotetrameric enzymes [1]
DSF pretreatment significantly increased ROS levels in cultured H9C2 cardiomyocytes subjected to high glucose stress compared to DSF-untreated cells presented with equimolar concentrations of glucose or mannitol
We report that the pharmacological inhibition of ALDH2 potentiates high glucose induced deleterious effects in cultured H9C2 cardiomyocyte cell lines
Summary
ALDH enzymes metabolize aldehydes into carboxylic acids. These aldehydes include aliphatic and aromatic aldehydes from the environment, food, and those generated during cell metabolism. ALDH plays a major role in detoxifying reactive aldehydes. A single point mutation in ALDH2 greatly reduces ALDH2 activity in East Asians, which leads to accumulation of acetaldehyde and facial flushing [3] and other harmful effects [4]. This mutation is reportedly associated with diabetic complications [5] and coronary diseases in East Asians. It is suggested that the toxicity of reactive aldehydes plays main role in the pathogenesis
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