Mechanisms of acrolein-induced myocardial dysfunction: implications for environmental and endogenous aldehyde exposure
1 Institute of Molecular Cardiology, Department of Medicine, and 2 Department of Pharmacology, University of Louisville, and 3 Medical Service, Louisville Veterans Affairs Medical Center, Louisville, Kentucky Submitted 7 March 2007 ; accepted in final form 29 September 2007 Aldehydes are ubiquitous...
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Published in: | American journal of physiology. Heart and circulatory physiology 2007-12, Vol.293 (6), p.H3673-H3684 |
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Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
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Summary: | 1 Institute of Molecular Cardiology, Department of Medicine, and 2 Department of Pharmacology, University of Louisville, and 3 Medical Service, Louisville Veterans Affairs Medical Center, Louisville, Kentucky
Submitted 7 March 2007
; accepted in final form 29 September 2007
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 -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.
oxidative stress; myocardial contraction; protein adducts; aldehydes
Address for reprint requests and other correspondence: S. D. Prabhu, Medicine/Card |
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ISSN: | 0363-6135 1522-1539 |
DOI: | 10.1152/ajpheart.00284.2007 |