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Also the doses used in the different injury paradigms as well as the
routes of administration vary considerably. The mechanisms that
improve function, enhance regeneration and/or slow deteriora-
tion remain undetermined and similarly the reasons why some
studies have been less successful or even failed is also unclear.
Indeed many questions remain open and the jury is out as to
whether Epo will fulfill its putative potential - based on animal
studies - to be a “universal” therapy for brain diseases.
6
Heart
6.1 Endogenous Epo
Acts on the Heart
Epo is important during myocardial development and knockdown
of Epo or EpoR in mice results in reduction in the number of car-
diomyocytes (hypoplasia) and enhanced susceptibility to left ven-
tricular dilatation and cardiac death (
137, 138
). However this
phenotype may be largely rescued by restoration of EpoR produc-
tion in hematopoietic tissue (
139
). Attempts to localize the EpoR
within the heart have been made by dissecting the chick embryonic
heart into epicardium, myocardium, and endocardium (
140
).
These experiments revealed that endogenous Epo is most likely
produced by the epicardium whereas EpoR is present in embry-
onic myocardium. However, positive inotropic and lusitropic
effects of Epo have been later recorded in isolated human epicar-
dial stripes indicating that adult human and mouse epicardium
responds to Epo (
141
). Changes in contractile force, but not in
contractile rate, were reported for isolated denervated rat heart
perfused with Krebs-Henseleits saline (
142
).
Epo receptors and functional responses to Epo were shown in iso-
lated cardiomyocytes (
141, 143-146
) coronary endothelial cells
(
83, 147
) and fibroblasts (
148
). The cardiac EpoR was shown to
respond equally efficiently to Epo, carbomylated Epo (CEPO), and
ARA-290 (
141, 149, 150
), a synthetic Epo mimetic comprised only
of helix B part of the cytokine. This synthetic non-erythropoietic
peptide was shown to activate the heteroreceptor, composed of an
EpoR subunit and bCR, but not the classical EpoR homodimer
(
79
). These findings suggest that the effects of Epo in the heart are
most likely mediated by such a heteroreceptor. Indeed expression of
bCR in the heart and the lack of Epo effect in bCR knockout myo-
cardium was shown (
79
).
Whereas in hematopoietic lineage EpoR expression is induced
by GATA-1, Sp1, and Wt1 transcription factors (
151, 152
), expres-
sion of the common EpoR subunits in the heart is under control of
GATA-4 and Sp1 transcription factors (
145
). The role of Wt1
expressed only in epicardium in regulation of EpoR expression
remains to be clarified (
153
). Induction of EpoR expression has
been observed in the failing ischemic heart and is most likely linked
to the stabilization of HIF that is downregulated in aging tissues.
6.2
EpoR in the Heart
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