title: Impaired ALDH2 activity decreases the mitochondrial respiration in H9C2 cardiomyocytes.
abstract: Reactive oxygen species (ROS)-mediated reactive aldehydes induce cellular stress. In cardiovascular diseases such as ischemia-reperfusion injury, lipid-peroxidation derived reactive aldehydes such as 4-hydroxy-2-nonenal (4HNE) are known to contribute to the pathogenesis. 4HNE is involved in ROS formation, abnormal calcium handling and more importantly defective mitochondrial respiration. Aldehyde dehydrogenase (ALDH) superfamily contains NAD(P)(+)-dependent isozymes which can detoxify endogenous and exogenous aldehydes into non-toxic carboxylic acids. Therefore we hypothesize that 4HNE afflicts mitochondrial respiration and leads to cell death by impairing ALDH2 activity in cultured H9C2 cardiomyocyte cell lines. H9C2 cardiomyocytes were treated with 25, 50 and 75 μM 4HNE and its vehicle, ethanol as well as 25, 50 and 75 μM disulfiram (DSF), an inhibitor of ALDH2 and its vehicle (DMSO) for 4 h. 4HNE significantly decreased ALDH2 activity, ALDH2 protein levels, mitochondrial respiration and mitochondrial respiratory reserve capacity, and increased 4HNE adduct formation and cell death in cultured H9C2 cardiomyocytes. ALDH2 inhibition by DSF and ALDH2 siRNA attenuated ALDH2 activity besides reducing ALDH2 levels, mitochondrial respiration and mitochondrial respiratory reserve capacity and increased cell death. Our results indicate that ALDH2 impairment can lead to poor mitochondrial respiration and increased cell death in cultured H9C2 cardiomyocytes.
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, USA.
authors.forename: Vishal R
authors.initials: VR
authors.lastname: Mali
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: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, USA.
authors.forename: Guodong
authors.initials: G
authors.lastname: Pan
authors.affiliation: Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: Rajarajan A
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. Electronic address: spalani2@hfhs.org.
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Palaniyandi
mesh_terms: D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D000447:Aldehydes / Q000633:toxicity; D000818:Animals; D016923:Cell Death; D002460:Cell Line; D019069:Cell Respiration / Q000187:drug effects; D018736:DNA Adducts / Q000378:metabolism; D004221:Disulfiram / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D051381:Rats
chemical_list: D000447:Aldehydes; D018736:DNA Adducts; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C027576:4-hydroxy-2-nonenal; D004221:Disulfiram
keywords: 4-Hydroxy-2-nonenal; Aldehyde dehydrogenase-2; Cell death; H9C2 cardiomyocytes; Mitochondrial respiration; Mitochondrial respiratory reserve capacity