期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 50, 期 3, 页码 570-577出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.yjmcc.2010.11.013
关键词
Oxidative stress; LTC4; Cys-LT1-receptor; MRP1; Myocardial injury
资金
- Deutsche Forschungsgemeinschaft [MU 1731/1-1]
- BONFOR
Tissue damage leads to release of pro-inflammatory mediators. Among these, leukotriene C-4 (LT) is a powerful, intracellularly induced mediator of inflammation, which requires inside-out transport of LTC4. We investigated whether release of LTC4 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 LTC4 caused enhanced rates of reactive oxygen species (ROS) release measured via L012-luminescence method and apoptosis. Pharmacologic LTC4 receptor blockade antagonized this effect in vitro. To evaluate the relevance of MRP1 mediated LTC4 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, LTC4 serum concentrations and levels of cellular apoptosis were increased in myocardial ayosections of FVB WT mice as compared to MRP1(-/-) mice. To identify key targets for pharmacological inhibition of LTC4, 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 (WTMontelukast: 40 +/- 5%, WTMK571: 39 +/- 3%, WTvehicle: 33 +/- 3% and decrease of AMM (WTMontelukast: 12 +/- 1%, WTMK571: 10 +/- 3% WTvehicle: 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. (C) 2010 Elsevier Ltd. All rights reserved.
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