NEUTROPHILS IN ACUTE CORONARY ARTERY DISEASE


Janos G. Filep, M.D., Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada

Neutrophil granulocytes are present in atherosclerotic lesions and contribute to inflammatory tissue injury underlying all phases of atherosclerosis from nascent lesions to culmination in acute coronary artery disease (CAD). Acute CAD is characterized by widespread neutrophil accumulation, neutrophil infiltration of culprit lesions and prolonged neutrophil lifespan. Elevated plasma levels of the neutrophil granule component myeloperoxidase (MPO) predict adverse cardiac outcomes in patients with CAD. MPO-derived oxidants are important mediators of neutrophil-mediated tissue injury. MPO also binds to the beta-2 integrin Mac-1 and generates survival cues for neutrophils by preserving expression of the anti-apoptotic protein Mcl-1. Emigrated neutrophils die via apoptosis, which is critical for timely resolution of inflammation and minimizing tissue damage. Treatment of human neutrophils with the pro-resolving lipid mediators aspirin-triggered 15-epi-lipoxin A4 or the omega- -3 fatty acid eicosapentaenoic acid-derived resolvin E1acting through formyl-peptide receptor FPR2 or the leukotriene B4 receptor BLT1, respectively, effectively countered the powerful anti-apoptosis signal from MPO and redirect neutrophils to apoptosis. These lipid mediators also promoted resolution of MPO-dependent inflammation in mice parallel with enhancing neutrophil apoptosis. Pharmacological inhibition of caspase activation prevented neutrophil death and aggravated tissue injury. Our results provide a potential link between MPO, neutrophil survival and acute CAD. These data also suggest that therapeutic induction of neutrophil apoptosis by pro-resolving lipid mediators may represent a novel approach for reducing neutrophil-mediated tissue injury and/or promoting the resolution of inflammation underlying acute CAD. (Grant support: CIHR).