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Fig. 2
The tissue protective region of EPO resides on the outer portion of helix B.
Helix B is not involved in binding to the hematopoietic receptor dimer.
Boxed sites
1 and 2
correspond to the high and low affinity binding sites of the receptor for EPO
respectively. The
circled region
of helix B delimits the tissue protective region from
which peptide analogues have been designed (reproduced from ref.
21
)
concentration range such that EPO occupies and activates both
receptor types. As previously mentioned, the hematopoietic recep-
tor is not restricted only to red cell development, as the endothe-
lium is also activated into a prothrombotic state, and highly
reactive, young platelets are produced by the bone marrow.
Therefore, several potential side effects of the use of renal EPO for
tissue protection are excessive erythropoiesis and thromboses.
These adverse effects have been clearly observed in large clinical
trials using EPO. As one example, a multicenter trial examining
the use of EPO in critical medical and surgical cases showed a
significant tissue protective effect in trauma patients, but at the
expense of an increased incidence of thromboses (
20
). These
adverse effects would be especially problematic in any chronic use
of EPO as a treatment of tissue injury.
A solution to this therapeutic conundrum was developed by
successfully altering the EPO molecule so as not to bind to the
hematopoietic receptor in a way that retained its full tissue protec-
tive activities (
15
). The existence of selective protective molecules
also suggested that a specific region of EPO was responsible for
tissue protection. Of note, when EPO binds to the hematopoietic
receptor, a large portion of the molecule is either buried or involved
in binding to the receptor. The remaining portion of the molecule
(helix B) faces away from the interior of the (Fig.
2
; ref.
21
). A
biological significance for helix B can be further appreciated by
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