| First Author | Becher UM | Year | 2011 |
| Journal | J Mol Cell Cardiol | Volume | 50 |
| Issue | 3 | Pages | 570-7 |
| PubMed ID | 21112334 | Mgi Jnum | J:171020 |
| Mgi Id | MGI:4948206 | Doi | 10.1016/j.yjmcc.2010.11.013 |
| Citation | Becher UM, et al. (2011) Inhibition of leukotriene C4 action reduces oxidative stress and apoptosis in cardiomyocytes and impedes remodeling after myocardial injury. J Mol Cell Cardiol 50(3):570-7 |
| abstractText | Tissue damage leads to release of pro-inflammatory mediators. Among these, leukotriene C(4) (LTC(4)) is a powerful, intracellularly induced mediator of inflammation, which requires inside-out transport of LTC(4). We investigated whether release of LTC(4)via the multidrug resistance related protein 1 (MRP1) induces apoptosis in cardiomyocytes in vitro and in vivo. Methods and results: Incubation of cultured embryonic cardiomyocytes (eCM) with recombined LTC(4) caused enhanced rates of reactive oxygen species (ROS) release measured via L012-luminescence method and apoptosis. Pharmacologic LTC(4) receptor blockade antagonized this effect in vitro. To evaluate the relevance of MRP1 mediated LTC(4) release after myocardial injury in vivo, MRP1(-/-) mice and FVB wildtype mice (WT) received cryoinjury of the left ventricle. Fourteen days after injury, left-ventricular ejection fraction (EF), end-diastolic volume (EDV), and akinetic myocardial mass (AMM) were quantified via echocardiography. MRP1(-/-) mice demonstrated increased EF (MRP1(-/-): 39 +/- 3%, WT: 29 +/- 4%) and reduced AMM (MRP1(-/-): 13 +/- 2% WT: 16 +/- 4%), indicating reduced post-infarction remodeling. Mechanistically, LTC(4) serum concentrations and levels of cellular apoptosis were increased in myocardial cryosections of FVB WT mice as compared to MRP1(-/-) mice. To identify key targets for pharmacological inhibition of LTC(4) actions, WT mice were treated with the specific Cys-LT1-receptor blocker Montelukast or the MRP1-Inhibitor MK571. Treatment of WT mice resulted in significant increase of EF (WT(Montelukast): 40 +/- 5%, WT(MK571): 39 +/- 3%, WT(vehicle): 33 +/- 3% and decrease of AMM (WT(Montelukast): 12 +/- 1%, WT(MK571): 10 +/- 3%, WT(vehicle): 15 +/- 5%) compared to untreated WT mice. Conclusion: Inhibition of leukotriene C(4) reduces levels of oxidative stress and apoptosis and demonstrates beneficial effects on myocardial remodeling after left ventricular injury. |
