title: Cardiac toxic effects of trans-2-hexenal are mediated by induction of cardiomyocyte apoptotic pathways.
abstract: Aldehydes are ubiquitous pollutants with well-indicated but ill-defined cardiovascular toxicity. To investigate the direct toxic effects of environmental aldehyde exposure on the myocardium, 8-wk-old male ICR (Institute of Cancer Research) strain mice were gavage fed trans-2-hexenal (0.1, 1, 10, or 50 mg/kg/wk) or corn oil (vehicle) for 4 wk, during which cardiac function, myocardial morphology, cardiomyocyte apoptosis, and the cytochrome cmediated caspase activation apoptotic pathway were determined. Quantification by enzyme-linked immunosorbent assay (ELISA) revealed that aldehyde- protein adducts increase in mouse hearts following hexenal treatment, whereas echocardiographic analysis displayed a significant impairment of basal left-ventricular contractile function. Both histological analysis and TUNEL (terminal deoxynucleotidyl transferase-mediated nick-end labeling) staining indicated condensed nuclei and a significant increase in cardiomyocyte apoptosis in these mice, but immunohistochemistry-based confocal microscope revealed no marked myofibril disarray. Release of cytochrome c from mitochondria into the cytosol, concomitant with activation of caspase-3 and -9, was also found in hexenal-treated groups. In addition, isolated cardiac mitochondria formed hexenal-protein adducts when treated with hexenal, providing indirect evidence that the cardiac mitochondrion is one of primary subcellular targets of aldehyde toxins. These findings suggest that trans-2-hexenal exposure results in direct cardiac toxicity through, at least in part, induction of mitochondrial cytochrome c release-mediated apoptosis in cardiomyocytes, indicating that the cardiac mitochondrion is one of principal subcellular targets of aldehyde toxins.
authors.affiliation: Department of Physiology, David Geffen School of Medicine at University of California, Los Angeles, USA.
authors.forename: Peipei
authors.initials: P
authors.lastname: Ping
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Baines
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
authors.forename: Sumanth D
authors.initials: SD
authors.lastname: Prabhu
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Linda L
authors.initials: LL
authors.lastname: Tsai
authors.forename: Ernest
authors.initials: E
authors.lastname: Cardwell
authors.forename: Nobel C
authors.initials: NC
authors.lastname: Zong
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Vondriska
authors.forename: Paavo
authors.initials: P
authors.lastname: Korge
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.forename: Guang-Wu
authors.initials: GW
authors.lastname: Wang
mesh_terms: D000185:Actinin / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000447:Aldehydes / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D004789:Enzyme Activation; D006331:Heart Diseases / Q000139:chemically induced*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008853:Microscopy; D008929:Mitochondria, Heart / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D011506:Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D000447:Aldehydes; D004785:Environmental Pollutants; D011506:Proteins; D000185:Actinin; C051750:2-hexenal; D045304:Cytochromes c; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases