Endogenous generation and protective effects of nitro-fatty acids in a murine model of focal cardiac ischaemia and reperfusion.
OBJECTIVE
Nitrated fatty acids (NO(2)-FA) have been identified as endogenous anti-inflammatory signalling mediators generated by oxidative inflammatory reactions. Herein the in vivo generation of nitro-oleic acid (OA-NO(2)) and nitro-linoleic acid (LNO(2)) was measured in a murine model of myocardial ischaemia and reperfusion (I/R) and the effect of exogenous administration of OA-NO(2) on I/R injury was evaluated.


RESULTS
In C57/BL6 mice subjected to 30 min of coronary artery ligation, endogenous OA-NO(2) and LNO(2) formation was observed after 30 min of reperfusion, whereas no NO(2)-FA were detected in sham-operated mice and mice with myocardial infarction without reperfusion. Exogenous administration of 20 nmol/g body weight OA-NO(2) during the ischaemic episode induced profound protection against I/R injury with a 46% reduction in infarct size (normalized to area at risk) and a marked preservation of left ventricular function as assessed by transthoracic echocardiography, compared with vehicle-treated mice. Administration of OA-NO(2) inhibited activation of the p65 subunit of nuclear factor kappaB (NFkappaB) in I/R tissue. Experiments using the NFkappaB inhibitor pyrrolidinedithiocarbamate also support that protection lent by OA-NO(2) was in part mediated by inhibition of NFkappaB. OA-NO(2) inhibition of NFkappaB activation was accompanied by suppression of downstream intercellular adhesion molecule 1 and monocyte chemotactic protein 1 expression, neutrophil infiltration, and myocyte apoptosis.


CONCLUSIONS
This study reveals the de novo generation of fatty acid nitration products in vivo and reveals the anti-inflammatory and potential therapeutic actions of OA-NO(2) in myocardial I/R injury.
Rudolph
Volker
V
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA. vrudolph@pitt.edu
Rudolph
Tanja K
TK
Schopfer
Francisco J
FJ
Bonacci
Gustavo
G
Woodcock
Steven R
SR
Cole
Marsha P
MP
Baker
Paul R S
PR
Ramani
Ravi
R
Freeman
Bruce A
BA
D000478:Alkylation; D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D004452:Echocardiography; D005227:Fatty Acids / Q000378:metabolism*; D007249:Inflammation / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D020556:Neutrophil Infiltration; D009569:Nitric Oxide / Q000378:metabolism*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism
D005227:Fatty Acids; D013859:Thiocarbamates; D051996:Transcription Factor RelA; C066229:prolinedithiocarbamate; D009569:Nitric Oxide; D011392:Proline