Biology Reference
In-Depth Information
phosphorylation of Akt and eNOS - its effects are seen within
5 min (
147
) and can be observed for the first hour and thereafter
the Epo-EpoR complex is internalized and degraded (Mihov,
Tavakoli, Bogdanova unpublished observations). The internaliza-
tion rate constant for Epo-EpoR complex in UT-7/Epo cells is
0.06 min
−1
(
172
). Upon internalization 60% of Epo gets dissoci-
ated from the classical EpoR homodimer and recycled, whereas
40% undergoes degradation (
172
). This observation suggests the
effect of Epo is transient with the amount of surface-based recep-
tors decreasing upon interaction with the cytokine.
Recent trials were performed in which very high doses of Epo were
administered percutaneously in patients after they were diagnosed
for myocardial infarction. The expected cardioprotective effects
included pro-angiogenic, anti-inflammatory, anti-apoptotic, and
anti-oxidative action of Epo which have been reported in animal
models of myocardial infarction (
173-175
). However these trials
showed no beneficial effects of Epo, and in several cases an increase
in mortality and morbidity was observed due to an increased risk of
thrombosis (
176-179
).
Possible reasons for the lack of Epo effect include the inadequate
route of the cytokine administration (intravenous vs. intramyocardial
vs. intraperitoneal vs. subcutaneous); lack of cofactors and ligands of
NO synthases (
L
-arginine, tetrabiopterin, oxygen) (
180-182
) and a
limited “window of cardioprotective effect,” which was claimed to be
wide, but has never been properly determined in the heart. Epo-
induced activation of NOSes in their uncoupled mode, due to the
shortage of substrates and cofactors, turns these enzymes from cardio-
protective anti-oxidative ones to cardiotoxic and pro-oxidative (
181,
183, 184
). Ischemia-reperfusion of coronary vessels is associated with
activation of arginase-1 in the endothelium and local reduction in
arginine availability (
185
). Oxygen deprivation inhibits eNOS and
nNOS since their affinity to this substrate is rather low (
186
).
As the outcome of the first Epo trials appeared to be so dis-
couraging an alternative approach has been suggested to increase
the cytokine efficacy. Cardioplegic solutions widely used in cardiac
surgery to cause heart arrest are now designed to induce activation
of endogenous Epo production in the arrested organ (
187
).
6.4 Epo in Treatment
of Cardiovascular
Diseases
7
Pancreas
Epo deficiency and higher incidence of anemia in individuals with
diabetes gave the first inkling of potential beneficial effects and
therapeutic applications of Epo use in the diabetes setting. Several
clinical studies reported a beneficial effect of recombinant Epo on
glucose metabolism in patients undergoing hemodialysis. Epo
treatment of patients with end-stage renal disease corrected lipid
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