UV light synergistically enhances the cardiotoxic effects of interleukin 1beta through peroxynitrite formation.
BACKGROUND
Proinflammatory cytokines play an important role in chronic cardiac diseases.


RESULTS
Neonatal rat cardiomyocytes were exposed to interleukin (IL)-1beta (2 ng/mL) for 4 days. We assessed contractility through videomicroscopy and calcium transients with the Ca(2+)-sensitive dye fura-2. In IL-1beta-treated cells, the UV excitation (380 nm) necessary to induce dye fluorescence effected a rapid cessation of Ca(2+) transients and contraction, accompanied by calcium overload originating from an intracellular compartment. This occurred in the absence of fura-2 but required UV illumination. Incubation with 10 mmol/L N-acetylcysteine prevented this response, suggesting a free radical-mediated event. However, exposure to IL-1beta either increased or did not change the activity of the free radical scavengers superoxide dismutase, catalase, and glutathione peroxidase. In contrast, lipid peroxidation increased by 600% (P < or =.0001) in the IL-1beta plus UV-treated cells, an effect eliminated by L-NMMA. L-NMMA also completely abolished the UV-mediated cytotoxicity. We used immunohistochemistry to localize nitrotyrosine accumulation in the myocytes cotreated with IL-1beta and UV, an effect that was also blocked by L-NMMA.


CONCLUSIONS
We hypothesize that the toxic radical peroxynitrite, arising from nitric oxide and superoxide anion, may be responsible for tetany and acute cardiomyocyte death. These results demonstrate the potential role of peroxynitrite in cardiotoxicity, which may be important in cardiac diseases associated with proinflammatory cytokines.
Combes
A
A
Cardiovascular Research Laboratories, Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.
McTiernan
C
C
Brooks
S S
SS
Feldman
A M
AM
D000818:Animals; D000831:Animals, Newborn; D009202:Cardiomyopathies / Q000378:metabolism*; D004357:Drug Synergism; D006706:Homeostasis / Q000502:physiology / Q000528:radiation effects; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000009:adverse effects* / Q000528:radiation effects*; D018715:Microscopy, Video; D009200:Myocardial Contraction / Q000502:physiology / Q000528:radiation effects*; D009566:Nitrates / Q000009:adverse effects* / Q000528:radiation effects*; D016877:Oxidants / Q000009:adverse effects* / Q000528:radiation effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014466:Ultraviolet Rays / Q000009:adverse effects*
D007375:Interleukin-1; D009566:Nitrates; D016877:Oxidants; C039642:peroxynitric acid