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.
Copyright (c) 2009 Elsevier Ltd. All rights reserved.