Abstract 12413: 5-Lipoxygenase Facilitates Healing after Myocardial Infarction
Background: Early healing after myocardial infarction (MI) is characterized by a strong inflammatory reaction. Most leukotrienes are pro-inflammatory and are therefore potential mediators of cardiovascular diseases. The enzyme 5-lipoxygenase (5-LOX) has a key role for the transformation of arachidonic acid in leukotrienes. Thus, we tested the effect of 5-LOX on healing after MI.
Methods and results: After coronary artery ligation mortality was significantly increased in 5-LOX-/- when compared to matching wildtype mice due to left ventricular rupture (WT vs. 5-LOX-/-, 41 vs. 86%, p<0.01). The effect could be reproduced in mice treated with the 5-LOX inhibitor Zileuton (50mg/kg bodyweight, po bid). One reason for healing defects after MI could be a circulation mismatch due to the vasoactive potential of leukotrienes. To test local blood flow we performed perfusion measurements by magnetic resonance imaging (7T-MRI). However, myocardial perfusion in the infarct or remote myocardium was not different between WT and 5-LOX-/- animals (remote, WT vs. 5-LOX-/-, 5.72±1.3 vs. 5.00±1.9 ml*g-1*min-1, p=n.s.). After MI pro-inflammatory proteins and pro-inflammatory monocyte infiltration were differentially regulated (monocyte subset, FACS analysis, WT vs. 5-LOX-/-, 41±6 vs. 66±2%, p<0.01). However, mortality was not changed in chimeric mice (WT vs. 5-LOX-/- bone marrow in 5-LOX-/- animals) indicating that an altered function of inflammatory cells is not responsible for the phenotype. Extracellular matrix remodeling was significantly altered in 5-LOX-/- mice in vivo after MI. Accordingly, in vitro migration of 5-LOX-/- fibroblasts was significantly impaired.
Conclusion: A lack or inhibition of 5-LOX increases mortality after myocardial infarction due to healing defects. This is not mediated by a change in local blood flow or inflammation, but through an altered fibroblast function.
- © 2011 by American Heart Association, Inc.