title: Cysteinyl leukotriene signaling aggravates myocardial hypoxia in experimental atherosclerotic heart disease.
abstract: BACKGROUND
  Cysteinyl-leukotrienes (cys-LT) are powerful spasmogenic and immune modulating lipid mediators involved in inflammatory diseases, in particular asthma. Here, we investigated whether cys-LT signaling, in the context of atherosclerotic heart disease, compromises the myocardial microcirculation and its response to hypoxic stress. To this end, we examined Apoe(-/-) mice fed a hypercholesterolemic diet and analysed the expression of key enzymes of the cys-LT pathway and their receptors (CysLT1/CysLT2) in normal and hypoxic myocardium as well as the potential contribution of cys-LT signaling to the acute myocardial response to hypoxia.
  
  
  RESULTS
  Myocardial biopsies from Apoe(-/-) mice demonstrated signs of chronic inflammation with fibrosis, increased apoptosis and expression of IL-6, as compared to biopsies from C57BL/6J control mice. In addition, we found increased leukotriene C(4) synthase (LTC(4)S) and CysLT1 expression in the myocardium of Apoe(-/-) mice. Acute bouts of hypoxia further induced LTC(4)S expression, increased LTC(4)S enzyme activity and CysLT1 expression, and were associated with increased extension of hypoxic areas within the myocardium. Inhibition of cys-LT signaling by treatment with montelukast, a selective CysLT1 receptor antagonist, during acute bouts of hypoxic stress reduced myocardial hypoxic areas in Apoe(-/-) mice to levels equal to those observed under normoxic conditions. In human heart biopsies from 14 patients with chronic coronary artery disease mRNA expression levels of LTC(4)S and CysLT1 were increased in chronic ischemic compared to non-ischemic myocardium, constituting a molecular basis for increased cys-LT signaling.
  
  
  CONCLUSIONS
  Our results suggest that CysLT1 antagonists may have protective effects on the hypoxic heart, and improve the oxygen supply to areas of myocardial ischemia, for instance during episodes of sleep apnea.
authors: Monzino Cardiologic Center, IRCCS, Milan, Italy.
authors: Elena
authors: E
authors: Nobili
authors: M Dolores
authors: MD
authors: Salvado
authors: Lasse
authors: L
authors: Folkersen
authors: Laura
authors: L
authors: Castiglioni
authors: Jens
authors: J
authors: Kastrup
authors: Anders
authors: A
authors: Wetterholm
authors: Elena
authors: E
authors: Tremoli
authors: Göran K
authors: GK
authors: Hansson
authors: Luigi
authors: L
authors: Sironi
authors: Jesper Z
authors: JZ
authors: Haeggström
authors: Anders
authors: A
authors: Gabrielsen
mesh_terms: D000368:Aged; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000150:complications*; D015687:Cell Hypoxia; D003545:Cysteine / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D015289:Leukotrienes / Q000378:metabolism*; D008297:Male; D051379:Mice; D017202:Myocardial Ischemia / Q000150:complications* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D018077:Receptors, Leukotriene / Q000235:genetics; D015398:Signal Transduction; D013312:Stress, Physiological; D015854:Up-Regulation
chemical_list: D001057:Apolipoproteins E; D015289:Leukotrienes; D018077:Receptors, Leukotriene; C112381:cysteinyl-leukotriene; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase; D003545:Cysteine; C083169:leukotriene D4 receptor