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In agreement heat-induced stabilization of HIF1a in the heart is
also associated with an increase of EpoR in the heart (
151
). Thus
down-regulation of various transcription factors may reduce the
efficiency of myocardial Epo treatment. Changes in EpoR expres-
sion during myocardial development and as a function of age
remain to be investigated. Regulators of expression of bCR in the
heart have also not been studied.
6.3 Where Does Epo
Act and What Are Its
Targets?
The source of Epo for receptor activation in the myocardium
remains unknown. Plasma-borne Epo most likely does not reach
cardiomyocytes (
147
). Thus, the cytokine should be generated by
one or more cell types within the myocardium and then be released
for autocrine/paracrine receptor activation similar to that in the
brain (Fig.
2
, pathway 7). In zebrafish, heart and liver were shown
to be the major Epo-producing organs (
154
). Although myocar-
dial Epo expression may be induced by hypoxic exposure (
155
) the
origin of endogenous Epo secreting cells in the mammalian heart
is unknown.
Localization of Epo action depends on the route of its admin-
istration/secretion. When applied intravenously Epo interacts
primarily with EpoR of endothelial cells of coronary vessels (Fig.
2
,
pathway 1) (
83, 147
). Thereby, cardioprotection of the plasma-
borne Epo is mediated by factors secreted from the endothelium
upon activation of endothelial EpoR (Fig.
2
, pathways 2 and 3).
Amongst these factors are endothelin-1 and NO (
156
). When
applied directly to isolated cardiomyocytes, Epo was shown to pro-
mote mitogenesis of neonatal cardiomyocytes, affect Ca
2+
handling
in isolated cells causing an increase in the amplitude and reduction
in duration of calcium transients, and protecting them from oxida-
tive stress and doxorubicin-induced apoptosis (Fig.
2
, pathways 6
and 7) (
141, 157-159
).
An exhaustive overview of the molecular mechanisms of cardio-
protective effects of erythropoietin can be found in recent reviews
(
160-162
). As mentioned above, the cardiac-specific receptor is
most likely a heterodimer. The downstream elements of signaling
cascades induced by activation of such a heteroreceptor remain
largely unknown. Also current data on the molecular mechanisms
of the cardioprotective action of Epo comes from observations of
the downstream effects of Epo in the heart. This is characteristic of
most of the studies performed to date in which observations fit into
the pre-existing model of homodimer function in erythroid precur-
sor cells (see Fig.
1
). To what extent activation pathways for the
homo- and heterodimer are similar remains unknown.
6.3.1 Acute Responses:
PI3-Akt-eNOS Signaling
Several studies indicated that the action of Epo in the heart is asso-
ciated with activation of PI3K-Akt pathway with subsequent
up-regulation of NO production (
83, 160, 163, 164
). Endothelial
NO synthase (eNOS) is localized in the caviolae of cardiomyocytes
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