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group of rats. Accordingly, at 4 weeks, in the DA group, left
ventricular function was better compared to controls.
Tamareille et al. (
44
) studied rats after 45 min ischemia and
24 h of reperfusion. The control group was compared with isch-
emic post-conditioning (three cycles of 10 s reperfusion/10 s isch-
emia) and EPO (1,000 IU/kg i.v.) at the onset of reperfusion.
EPO decreased significantly more infarct size and transmurality
than ischemic post-conditioning.
Miki et al. (
45
) tested the hypothesis that endoplasmic reticu-
lum stress in diabetic hearts impairs phospho-glycogen synthase
kinase (GSK)-3beta-mediated suppression of mitochondrial per-
meability transition pore (mPTP) opening, compromising myocar-
dial response to cytoprotective signaling. Infarction was induced
by 20-min coronary occlusion and 2-h reperfusion. Administration
of 5,000 U/kg of EPO 15 min before ischemia induced phospho-
rylation of Akt and GSK-3beta and reduced infarct size (percent
risk area) from in control hearts. However, neither phosphoryla-
tion of Akt and GSK-3beta nor infarct size limitation was induced
by EPO in rats with type 2 diabetes. The authors suggest that dis-
ruption of protective signals leading to GSK-3beta phosphoryla-
tion and increase in mitochondrial GSK-3beta are dual mechanisms
by which increased ER stress inhibits EPO-induced suppression of
mPTP opening and cardioprotection in diabetic hearts.
Infarct size after 20-min ischemia followed by 2-h reperfusion
was larger in a rat model of type 2 diabetes (Otsuka-Long-Evans-
Tokushima fatty (OLETF) rat) than in its control (
46
). Activation
of Jak2-mediated signaling by erythropoietin, given 15 min before
ischemia (dose and route of administration not reported), limited
infarct size in control rats but not in OLETF rats. The results sug-
gest that the diabetic heart is refractory to protection by Jak2-
activating ligands such as EPO because of AT1 receptor-mediated
upregulation of calcineurin activity.
Treguer et al. (
47
) used speckle tracking imaging in a rat model
of ischemia-reperfusion to accurately detect the reduction of infarct
size and transmural extension of MI induced by 1,000 U/kg of
EPO i.v. as early as 24 h after reperfusion. A single bolus of EPO
was administered at the onset of reperfusion after 45 min ischemia.
EPO significantly decreased infarct size and transmural extension
of MI. None of the conventional echocardiography parameters was
significantly different between the MI-EPO and MI-control
groups. These results support the usefulness of speckle tracking
imaging in the early evaluation of a cardioprotective strategy in a
rat model of ischemia-reperfusion.
Shen et al. (
48
) studied the cardioprotective and anti-
inflammatory effects of EPO in a rat model of 30-min ischemia
followed by 3 h reperfusion. Rats receiving single i.v. boluses of
rhEPO of 100-5,000 IU/kg 30 min before ischemia exhibited
dose-dependent significant reduction in the incidence of ventricular
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