Article

Mechanisms of acrolein-induced myocardial dysfunction: implications for environmental and endogenous aldehyde exposure.

Institute of Molecular Cardiology, Department of Medicine, University of Louisville, 550 South Jackson Street, Louisville, KY 40202, USA.
AJP Heart and Circulatory Physiology (impact factor: 3.71). 12/2007; 293(6):H3673-84. DOI:10.1152/ajpheart.00284.2007 pp.H3673-84
Source: PubMed

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.

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Keywords

altering catecholamine sensitivity
 
cardiac alpha-actin
 
cardiac dysfunction
 
closed-chest mice
 
contractile dysfunction
 
direct exposure
 
drug metabolism
 
drug toxicity
 
energy metabolism
 
energy metabolism proteins
 
high-oxidative stress
 
intravenous acrolein
 
model unsaturated aldehyde acrolein
 
Myocardial dysfunction induced
 
myosin light polypeptide 3
 
organic materials
 
site-specific protein modification
 
thiol donor N-acetylcysteine
 
Two-dimensional gel electrophoresis
 
unsaturated aldehydes