title: Mechanisms of acrolein-induced myocardial dysfunction: implications for environmental and endogenous aldehyde exposure.
abstract: Aldehydes are ubiquitous pollutants generated during the combustion of organic materials and are present in air, water, and food. Several aldehydes are also endogenous products of lipid peroxidation and by-products of drug metabolism. Despite well-documented high reactivity of unsaturated aldehydes, little is known regarding their cardiovascular effects and their role in cardiac pathology. Accordingly, we examined the myocardial effects of the model unsaturated aldehyde acrolein. In closed-chest mice, intravenous acrolein (0.5 mg/kg) induced rapid but reversible left ventricular dilatation and dysfunction. In mouse myocytes, micromolar acrolein acutely depressed myofilament Ca(2+) responsiveness without altering catecholamine sensitivity, similar to the phenotype of stunned myocardium. Immunoblotting revealed increased acrolein-protein adducts and protein-carbonyls in both acrolein-exposed myocardium (1.8-fold increase, P < 0.002) and myocytes (6.4-fold increase, P < 0.02). Both the contractile dysfunction and adduct formation were markedly attenuated by pretreatment with the thiol donor N-acetylcysteine (5 mM). Two-dimensional gel electrophoresis and mass-assisted laser desorption/ionization time-of-flight mass spectrometry analysis revealed two groups of adducted proteins, sarcomeric/cytoskeletal proteins (cardiac alpha-actin, desmin, myosin light polypeptide 3) and energy metabolism proteins (mitochondrial creatine kinase-2, ATP synthase), indicating site-specific protein modification that was confirmed by immunohistochemical colocalization. We conclude that direct exposure to acrolein induces selective myofilament impairment, which may be, in part, related to the modification of proteins involved in myocardial contraction and energy metabolism. Myocardial dysfunction induced by acrolein and related aldehydes may be symptomatic of toxicological states associated with ambient or occupational exposures or drug toxicity. Moreover, aldehydes such as acrolein may mediate cardiac dysfunction in pathologies characterized by high-oxidative stress.
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, 550 South Jackson Street, Louisville, KY 40202, USA.
authors.forename: Jianzhu
authors.initials: J
authors.lastname: Luo
authors.forename: Bradford G
authors.initials: BG
authors.lastname: Hill
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
authors.forename: Jian
authors.initials: J
authors.lastname: Cai
authors.forename: Sanjay
authors.initials: S
authors.lastname: Srivastava
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.forename: Sumanth D
authors.initials: SD
authors.lastname: Prabhu
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use; D000171:Acrolein / Q000633:toxicity*; D000447:Aldehydes / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D020013:Calcium Signaling / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015180:Electrophoresis, Gel, Two-Dimensional; D004781:Environmental Exposure; D004785:Environmental Pollutants / Q000633:toxicity*; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D050050:Protein Carbonylation / Q000187:drug effects; D040901:Proteomics / Q000379:methods; D018570:Risk Assessment; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013438:Sulfhydryl Compounds / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D004785:Environmental Pollutants; D013438:Sulfhydryl Compounds; D000171:Acrolein; D000111:Acetylcysteine