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i.v. 500 U/kg either 90 min or 24 h and 90 min before coronary
occlusion. Infarct size as a proportion of the ischemic area was
measured in vivo by myocardial perfusion imaging (MPI) and
postmortem by a histochemical procedure (at 150 min of reperfu-
sion). Infarct size relative to the area at risk did not differ significantly
between control and EPO groups. These negative results in the pig
contrast with all positive results obtained in small rodents, even if
the authors cannot exclude possible beneficial effects at later times
on apoptosis and/or on left ventricular remodeling.
Liu et al. (
27
) further investigated mechanisms of the anti-
inflammatory action of EPO in a rat model of cardiac 30 min isch-
emia and 3 h reperfusion. Injection of 5,000 U/kg of rhEPO 24 h
before insult remarkably reduced infarct size and neutrophil
infiltration. EPO greatly attenuated ischemia-reperfusion-induced
NF-kB and AP-1 activation with decreased TNF-alpha, IL-6, andI-
CAM-1 production and enhanced the production of the anti-
inflammatory cytokine IL-10.
Nishihara et al. (
28
) showed that both preconditioning (PC)
with 5-min ischemia-5-min reperfusion and EPO (5,000 U/kg i.v.),
given 5 min before reperfusion reduced infarct size after 20-min
ischemia in rat hearts in situ followed 2 h of reperfusion. The results
suggest that EPO and PC afford additive infarct size-limiting effects
by additive phosphorylation of GSK-3beta at the time of reperfusion
by Akt-dependent and -independent mechanisms.
While high-dose EPO has been found to be cardioprotective in
experimental acute MI in small rodents, in large mammals, how-
ever, results are controversial and long-term follow-up data are
lacking. Olea et al. (
29
) assessed the long-term effects of high-dose
EPO on left ventricular infarct size and function in an ovine model
of reperfused MI. After 90 min of coronary occlusion, at the onset
of reperfusion, sheep received recombinant human erythropoietin
(rhEPO) 3,000 U/kg on 3 consecutive days (rhEPO group) or
vehicle (placebo group). Infarct size, evaluated as percent fibrotic
myocardium (morphometry) and by hydroxyproline quantification,
was similar in both groups. Left ventricular contractile function
was decreased in rhEPO group, compared to controls, left ventri-
cle was more dilated, and left ventricular end-diastolic pressure was
increased 10 weeks after coronary occlusion.
Liu et al. (
30
) studied the possible role of cyclooxygenase
(COX)-2 in the delayed phase of the cardioprotection induced by
recombinant human erythropoietin (rhEPO). Rats were given
5,000 U/kg i.p. of rhEPO 24 h before 30 min of ischemia fol-
lowed by 3 h of reperfusion. Infarct size reduction in rhEPO group
was abolished by the COX-2 inhibitor celecoxib given i.p. at the
dose of 5 mg/kg 24 h before ischemia. It appears that COX-2
plays an essential part in cardioprotection of the delayed phase of
EPO preconditioning in rats, which might be related to actions of
PGE(2) or PGI(2), or both.
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