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and is known to regulate the activity of
L
-type calcium channels by
phosphorylation and S-nitrosylation. Upon eNOS activation and
NO binding to soluble guanylyl cyclase, PKG-induced phosphory-
lation of contractile protein machinery is induced (
165
). These
effects of Epo were confirmed for isolated cells as well as in vivo in
hearts after intravenous Epo administration. In the latter case Akt
and eNOS phosphorylation is restricted to the endothelial cells of
coronary vessels (
147
). In cardiomyocytes the direct cytoprotective
effect of Epo is mediated by its regulatory action on calcium han-
dling and stabilization of the mitochondria. Epo induces activation
of eNOS in cavioli by its phosphorylation at Ser 1177 by Akt. The
generated NO then modulates activity of
L
-type Ca
2+
channels via
cGMP-sensitive phosphorylation and S-nitrosylation. Along with
the Ca
2+
release from the sarcoplasmic reticulum and SERCA2A the
calcium pump is activated in response to stimulation of iNOS by
Epo (
166, 167
). The exact molecular mechanisms of the action of
Epo on calcium dynamics in the heart tissue are still unknown,
however in myocardial stripes and in isolated cells (not on the ves-
sels) they were tracked down to the PI3K-sensitive activation of
PKCe (
141
). Stabilization of mitochondrial function in ischemic/
injured myocardium by Epo is mediated by the activation of the
mitochondrial KATP channels by Epo (
166, 167
). Furthermore,
uncoupling of the mitochondrial electron transduction chain is
reduced due to the interaction of iNOS-derived NO with the mito-
chondrial cytochromes. Mitochondrial biogenesis in cardiomyo-
cytes is promoted by Epo which in turn induces enhancement of
nuclear respiratory factor-1, PGC-1a (peroxisome proliferator-
activated receptor
coactivator 1a), and mitochondrial transcription
factor-A gene expression in wild-type but not in eNOS
−/−
or Akt1
−/−
mice (
168
). Thus till now, most of the cardioprotective effects of
Epo interaction with its receptor in cardiomyocytes seem to be
mediated via PI3K-Akt-eNOS pathway (see Fig.
1
).
Systemic induction of endogenous Epo production and release
is known to occur in response to hypoxic stimulation. All the above
mentioned responses of heart to Epo increase the survival proba-
bility during injury.
ϒ
Long-term activation of PI3K/Akt pathways in the heart induces
activation of insulin-like growth factor binding protein-5 and
downregulates peroxisome proliferator activated receptor-
6.3.2 Chronic
Responses: Changes
in Gene Expression
ϒ
(PPAR-
) coactivator-1 shifting metabolism from oxidative to
aerobic glycolytic during long-term ischemia (
169
). Similar repro-
gramming of metabolism was observed in hypoxic heart and dur-
ing pathological hypertrophic remodeling (
170
). Glucose delivery
in cardiac myocytes is up-regulated accordingly as expression of
Glut4 glucose transporter is induced along with metabolic repro-
gramming (
171
). Whether long term Epo treatment causes simi-
lar effects remains unclear. Epo binding to its receptors induces
ϒ
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