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Cysteinyl leukotriene signaling aggravates myocardial hypoxia in experimental atherosclerotic heart disease

Nobili, Elena ; Salvado, M Dolores ; Folkersen, Lasse ; Castiglioni, Laura ; Kastrup, Jens ; Wetterholm, Anders ; Tremoli, Elena ; Hansson, Göran K ; Sironi, Luigi ; Haeggström, Jesper Z ; Gabrielsen, Anders de Melo, Christianne Bandeira

PloS one, 2012-07, Vol.7 (7), p.e41786-e41786 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Cysteinyl leukotriene signaling aggravates myocardial hypoxia in experimental atherosclerotic heart disease
Autor: Nobili, Elena ; Salvado, M Dolores ; Folkersen, Lasse ; Castiglioni, Laura ; Kastrup, Jens ; Wetterholm, Anders ; Tremoli, Elena ; Hansson, Göran K ; Sironi, Luigi ; Haeggström, Jesper Z ; Gabrielsen, Anders
de Melo, Christianne Bandeira
Assuntos: Aged ; Animals ; Apnea ; Apolipoprotein E ; Apolipoproteins E - deficiency ; Apoptosis ; Arteriosclerosis ; Asthma ; Atherosclerosis ; Atherosclerosis - complications ; Biochemistry ; Biology ; Cardiovascular disease ; Cell Hypoxia ; Collagen ; Coronary artery ; Coronary artery disease ; Coronary heart disease ; Cysteine - metabolism ; Disease Models, Animal ; Enzymatic activity ; Enzyme activity ; Enzymes ; Ethnicity ; Female ; Fibrosis ; Gene expression ; Glutathione Transferase - genetics ; Heart ; Heart attacks ; Heart diseases ; House mouse ; Humans ; Hypercholesterolemia ; Hypoxia ; Inflammation ; Inflammatory diseases ; Interleukin 6 ; Ischemia ; Leukotriene-C4 synthase ; Leukotrienes ; Leukotrienes - metabolism ; Male ; Medical research ; Medicin och hälsovetenskap ; Medicine ; Medicine, Experimental ; Mice ; Montelukast ; Myocardial ischemia ; Myocardial Ischemia - complications ; Myocardial Ischemia - metabolism ; Myocardial Ischemia - pathology ; Myocardial Ischemia - physiopathology ; Myocardium ; Myocardium - metabolism ; Myocardium - pathology ; Oxygen ; Permeability ; Pharmacology ; Receptors ; Receptors, Leukotriene - genetics ; RNA ; Rodents ; Signal Transduction ; Signaling ; Sleep ; Sleep apnea ; Sleep apnea syndromes ; Sleep disorders ; Stress, Physiological ; Up-Regulation
É parte de: PloS one, 2012-07, Vol.7 (7), p.e41786-e41786
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Conceived and designed the experiments: EN ET GKH LS JZH AG. Performed the experiments: EN MDS LF LC JK AW LS AG. Analyzed the data: EN MDS LF LC JK AW ET GKH LS JZH AG. Contributed reagents/materials/analysis tools: JK ET GKH LS JZH AG. Wrote the paper: EN MDS LF LC JK AW ET GKH LS JZH AG.
Descrição: 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. 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. 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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