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Chemokine CCL5/RANTES inhibition reduces myocardial reperfusion injury in atherosclerotic mice

Weber, Christian
Proudfoot, Amanda
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Published in Journal of Molecular and Cellular Cardiology. 2010, vol. 48, no. 4, p. 789-798
Abstract Although beneficial for cardiomyocyte salvage and to limit myocardial damage and cardiac dysfunction, restoration of blood flow after prolonged ischemia exacerbates myocardial injuries. Several deleterious processes that contribute to cardiomyocyte death have been proposed, including massive release of reactive oxygen species, calcium overload and hypercontracture development or leukocyte infiltration within the damaged myocardium. Chemokines are known to enhance leukocyte diapedesis at inflammatory sites. The aim of the present study was to investigate the effect of chemokine CCL5/RANTES antagonism in an in vivo mouse model of ischemia and reperfusion. ApoE(-/-) mice were submitted to 30 min ischemia, by ligature of the left coronary artery, followed by 24 h reperfusion. Intraperitoneal injection of 10 mug of CCL5/RANTES antagonist [(44)AANA(47)]-RANTES, 5 min prior to reperfusion, reduced infarct size as well as Troponin I serum levels compared to PBS-treated mice. This beneficial effect of [(44)AANA(47)]-RANTES treatment was associated with reduced leukocyte infiltration into the reperfused myocardium, as well as decreased chemokines Ccl2/Mcp-1 and Ccl3/Mip-1alpha expression, oxidative stress, and apoptosis. However, mice deficient for the CCL5/RANTES receptor Ccr5 did not exhibit myocardium salvage in our model of ischemia-reperfusion. Furthermore, [(44)AANA(47)]-RANTES did not mediate cardioprotection in these ApoE(-/-) Ccr5(-/-) deficient mice, probably due to enhanced expression of compensatory chemokines. This study provides the first evidence that inhibition of CCL5/RANTES exerts cardioprotective effects during early myocardial reperfusion, through its anti-inflammatory properties. Our findings indicate that blocking chemokine receptor/ligand interactions might become a novel therapeutic strategy to reduce reperfusion injuries in patients during acute coronary syndromes.
Keywords AnimalsApolipoproteins E/metabolismApoptosisAtherosclerosis/*pathologyChemokine CCL5/*antagonists & inhibitors/metabolismChemokines/metabolismHumansIschemiaLeukocytes/metabolismMiceMice, TransgenicMyocardial Ischemia/pathologyMyocardial Reperfusion Injury/*pathologyReactive Oxygen Species/metabolismTroponin I/metabolism
PMID: 19665464
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Research groups Biologie du myocarde (22)
L'athérosclérose et ses complications cliniques (591)
Le rôle du système endocannabinoïde dans l'athérosclérose (882)
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BRAUNERSREUTHER, Vincent et al. Chemokine CCL5/RANTES inhibition reduces myocardial reperfusion injury in atherosclerotic mice. In: Journal of Molecular and Cellular Cardiology, 2010, vol. 48, n° 4, p. 789-798. doi: 10.1016/j.yjmcc.2009.07.029 https://archive-ouverte.unige.ch/unige:20801

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Deposited on : 2012-05-23

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