Università degli Studi di Milano   Archivio Istituzionale della Ricerca
Please use this identifier to cite or link to this item: http://hdl.handle.net/2434/207083

Title: Cysteinyl leukotriene signaling aggravates myocardial hypoxia in experimental atherosclerotic heart disease
Authors: NOBILI, ELENA (First author)
CASTIGLIONI, LAURA
TREMOLI, ELENA
SIRONI, LUIGI
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.
MIUR subjects: BIO/14 - Farmacologia
Project title: European Collaborative Project on Inflamation and Vascular Wall Remodelling (2008-PQ7-0007)
EU grant: FP7
Publication date: 25-Jul-2012
Digital Object Identifier (DOI): 10.1371/journal.pone.0041786
Research centers: Centro di Ricerche Farmacologiche per lo studio e la prevenzione delle Malattie Cardiovascolari
Citation: 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. e41786.1-e41786.9.
Pubmed identifier: 22848603
ISI identifier: 000306806600117
Scopus identifier: 84864363914
Type: Article (author)

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