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Burger et al. (
40
) investigated the role of heme-oxygenase
(HO)-1 in the anti-apoptotic effects of EPO in isolated fetal murine
cardiac myocytes and in vivo. Pretreatment with 2,500 U/kg i.v. of
EPO 24 h and 30 min before coronary ligation decreased infarct size
as well as ischemia-reperfusion-induced apoptosis in wild-type mice.
However, these effects were significantly diminished in HO-1(−/−)
mice. Furthermore, EPO given during ischemia reduced infarct size
in mice subjected to I/R, and this effect was blocked by chromium
mesoporphyrin, a selective inhibitor of HO-1, in wild-type mice.
Moreover, inhibition of p38 diminished the cardioprotective effects
of EPO. The authors conclude that upregulation of HO-1 expres-
sion via p38 signaling contributes to EPO-mediated cardioprotec-
tion during myocardial ischemia-reperfusion.
Burger et al. (
41
) studied in vivo the antiarrhythmic effects of
EPO: wild-type (WT) and nNOS null mice were anesthetized and,
after a baseline measurement, subjected to myocardial I/R to pro-
voke ventricular arrhythmias. Pretreatment with 2,500 U/kg of
i.v. EPO 24 h and 30 min before ischemia increased nNOS expres-
sion and significantly reduced the number of premature ventricular
contractions and the incidence of ventricular tachycardia in WT
mice. In contrast, treatment with EPO had no effect on premature
ventricular contractions or the incidence of ventricular tachycardia
in nNOS null mice.
French et al. (
42
) induced myocardial ischemia for 3 h in
10-week-old C57BL6 mice followed by 72 h of reperfusion.
EPO (10,000 U/kg) or an equivalent amount of saline vehicle
alone was injected i.p. before ligation or immediately after the
onset of reperfusion. Assays of residual left ventricular creatine
kinase (CK) activity and calculation of left ventricular CK deple-
tion were performed on left ventricular homogenates harvested
72 h after onset of reperfusion for measurement of infarct size,
and echocardiography was performed immediately before har-
vest of tissue for measurement of function. Both mice adminis-
tered EPO before ligation or after reperfusion had similar infarct
size and echo scores compared with those in control mice admin-
istered saline.
Schlecht-Bauer et al. (
43
) subjected rats to 40 min of coronary
artery ligation followed by 72 h or 4 weeks reperfusion and received
either darbepoetin (DA) (3-30 mg/kg) or vehicle prior to isch-
emia. In the DA groups reperfused for 72 h, left ventricular short-
ening fraction and left ventricular ejection fraction were higher
than that in the control rats, in agreement with a smaller left ven-
tricular infarct size. The cardioprotective effect of DA was dose-
dependent. DA treatment activated the JAK2/Akt signaling
pathway, lowered cleaved caspase-3, and increased both phospho-
rylated-Bad and phosphorylated-GSK-3beta proteins. This was
consistent with the decrease of reactive oxygen species production
and the lowered binding of Bad to Bcl-xL and Bcl-2 in a DA30
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