Myocardial Infarction: Cardioprotection by Erythropoietin - Tissue-Protective Cytokines: Methods and Protocols - page 275

arrhythmias caused by reperfusion, and markedly decreased serum
concentrations of IL-6, IL-8, and tumor necrosis factor-alpha
compared with the untreated group.
Stein et al. ( 49 ) comparatively assessed the beneficial effects of
intra-myocardial application of umbilical cord blood expanded
endothelial progenitor cells (eEPCs) and EPO as compared to
eEPCs or EPO alone in experimental MI. Nude rats underwent
ligation of the left anterior descending coronary artery for 30 min
followed by reperfusion. After intra-myocardial transplantation of
eEPC and 200 U of EPO, CD68+ leukocyte count and vessel den-
sity were enhanced in the border zone of the infarct area. Moreover,
apoptosis of transplanted CD31+TUNEL+eEPC was decreased
as compared to transplantation of eEPCs alone. Regional wall
motion of the left ventricle was measured using Magnetic Resonance
Imaging 4 weeks after infarction. After injection of eEPC in the
presence of EPO regional wall motion significantly improved as
compared to injection of eEPCs or EPO alone, while global ejec-
tion fraction was not affected. In conclusion, intra-myocardial
transplantation of eEPC in the presence of EPO during experi-
mental MI improves regional wall motion.
Yano et al. ( 50 ) induced MI by 20-min coronary occlusion fol-
lowed by 2 h reperfusion in spontaneously hypertensive stroke-
prone rats (SHR-SPs) and their controls (Wistar-Kyoto rats
(WKYs)). Infarct size expressed as a percentage of area-at-risk was
larger by 29% in SHR-SPs than in WKYs. Pretreatment with
5,000 U/kg of EPO i.v. 15 min before ischemia significantly lim-
ited infarct size in WKYs but not in SHR-SPs. The results suggest
that enhanced opening of mitochondrial permeability transition
pores by reactive oxygen species and modification of the signal
downstream of phospho-glycogen synthase kinase-3b in the mito-
chondria underlie the increased vulnerability to infarction and the
lack of anti-infarct tolerance by EPO, respectively, in hypertensive
hypertrophied hearts.
The straightforward clinical transferability of results obtained
in models of cardiac ischemia-reperfusion requires some final
comments.
In vivo animal studies with EPO in cardiac ischemia-reperfusion
model suggest the following:
1. Practically all studies on small rodents show that doses of
EPO as low as 100 U/kg reduce infarct size and improve left
ventricular function
2. Most dose regimens included a dose given before ischemia
(clinically unfeasible), other studies showed that EPO was
protective even when administered right before or even after
the onset of reperfusion ( 21, 38, 42 ); in one study the darbe-
poetin was effective even administered 24 h after the onset of
reperfusion ( 31 ).