title: ALDH2 Inhibition Potentiates High Glucose Stress-Induced Injury in Cultured Cardiomyocytes.
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 10μM 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.
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, USA.
authors.forename: Guodong
authors.identifier: 0000-0003-0594-4492
authors.initials: G
authors.lastname: Pan
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, USA.
authors.forename: Mandar
authors.initials: M
authors.lastname: Deshpande
authors.affiliation: Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: Rajarajan A
authors.identifier: 0000-0001-8452-2903
authors.initials: RA
authors.lastname: Thandavarayan
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, USA; Department of Physiology, Wayne State University, Detroit, MI 48202, USA.
authors.forename: Suresh Selvaraj
authors.identifier: 0000-0001-7559-8041
authors.initials: SS
authors.lastname: Palaniyandi
mesh_terms: D065086:Acetaldehyde Dehydrogenase Inhibitors / Q000494:pharmacology*; D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000037:antagonists & inhibitors*; D002460:Cell Line; D004221:Disulfiram / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009997:Osmotic Pressure / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D065086:Acetaldehyde Dehydrogenase Inhibitors; D017382:Reactive Oxygen Species; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D005947:Glucose; D004221:Disulfiram