Blocking cysteinyl leukotriene signalling ameliorates myocardial hypoxia in chronic ischemic heart disease

Background: The involvement of cysteinyl leukotrienes (cys-LTs) and their receptors (CysLTs receptor) in the pathologic response to chronic cardiac ischemia and during bouts of ischemia remains an unresolved question. Objective: We investigated the expression of cys-LT pathway components in normal and ischemic myocardium and the potential benefits of interrupting cys-LT signalling during bouts of ischemia. Methods and Results: Heart biopsies were collected from C57BL/6J control mice and Apoe-/- mice fed a hypercholesterolemic diet for 1 year and subjected to an hypoxic stimulus for 30 minutes. Contribution of leukotriene signalling to cardiac ischemia induced by hypoxia was evaluated by administration of montelukast, a selective CysLT1 receptor antagonist. We also used a unique collection of human heart biopsies obtained from normal and chronic ischemic areas of the myocardium of 14 patients with chronic coronary artery disease. Here we report that in myocardium of Apoe-/- mice, leukotriene C4 synthase (LTC4S) and CysLT1 are upregulated compared to C57BL/6J. Acute hypoxia further induced LTC4S expression and enzyme activity along with increased CysLT1 expression. Similar mRNA expression patterns of LTC4S and CysLT1 were observed in non-ischemic versus chronic ischemic human myocardium. Treatment of Apoe-/- mice with montelukast, during acute hypoxic stress, ameliorated myocardial hypoxic load to levels equal to those observed under normoxia. Conclusions: The data show an increased leukotriene signalling in chronic ischemic myocardium. In an experimental Apoe-/- model of ischemic cardiomyopathy, inhibition of leukotriene signalling ameliorates hypoxic damage to the myocardium suggesting a possible beneficial effect of antileukotriene drugs on the ischemic heart. Figure 1: LTC4S and CysLT1 are upregulated in cardiac tissue of Apoe-/- mice In the -/-Apoe-/- heart levels of LTC4S and CysLT1 are significantly upregulated as compared to control C57BL/6J mice (Panel A). Acute hypoxic stress in Apoe-/- mice increases the cardiac expression of LTC4S (p<0.05) and CysLT1 (p=0.06) compared to normoxic conditions (Panel B). Each experiment was run in duplicate and changes in mRNA levels were expressed as ΔΔCt values. Values are mean ± SD. *, p<0.05; **, p<0.01. References. [1] Gabrielsen A, Lawler PR, Yongzhong W, et al., Gene expression signals involved in ischemic injury, extracellular matrix composition and fibrosis defined by global mRNA profiling of the human left ventricular myocardium. J Mol Cell Cardiol. 42, 870-83, 2007. [2] Steffens S, Montecucco F, Mach F., The inflammatory response as a target to reduce myocardial ischaemia and reperfusion injury. Thromb Haemost,102, 240-7, 2009.