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. METHODS AND PRINCIPAL FINDINGS: 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. CONCLUSION: 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.

Cysteinyl leukotriene signaling aggravates myocardial hypoxia in experimental atherosclerotic heart disease / E. Nobili, M.D. Salvado, L. Folkersen, L. Castiglioni, J. Kastrup, A. Wetterholm, E. Tremoli, G. K. Hansson, L. Sironi, J. Z. Haeggström, A. Gabrielsen. - In: PLOS ONE. - ISSN 1932-6203. - 7:7(2012 Jul 25), pp. e41786.e41786.1-e41786.e41786.9. [10.1371/journal.pone.0041786]

Cysteinyl leukotriene signaling aggravates myocardial hypoxia in experimental atherosclerotic heart disease

E. Nobili
Primo
;
L. Castiglioni;E. Tremoli;L. Sironi;
2012

Abstract

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. METHODS AND PRINCIPAL FINDINGS: 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. CONCLUSION: 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.
Settore BIO/14 - Farmacologia
   European Collaborative Project on Inflamation and Vascular Wall Remodelling
   ATHEROREMO
   EUROPEAN COMMISSION
   FP7
   201668
25-lug-2012
Article (author)
File in questo prodotto:
File Dimensione Formato  
journal.pone.0041786.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 492.77 kB
Formato Adobe PDF
492.77 kB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/207083
Citazioni
  • ???jsp.display-item.citation.pmc??? 11
  • Scopus 26
  • ???jsp.display-item.citation.isi??? 24
social impact