Biology Reference
In-Depth Information
increased hematocrit in this cardiovascular-demanding sport) [40, 41]. (See
Chapter 13 for further information.)
Polycythemia vera, a myeloproliferative disease, is due to a clonal somatic
mutation in hematopoietic precursor cells that results in red cell overproduc-
tion independent of EPO regulation. The amount of circulating EPO may be
either normal or low. The increased red cell production, frequently associated
with concomitant increases in platelets and granulocytes, represents a clonal
proliferation at the level of the hematopoietic stem cell or CFU-GEMM. A
deregulated increase in the expression of the apoptosis inhibitor bcl-X
L
, possi-
bly due to a functional deletion of a negative-regulatory mechanism in signal
transduction, may allow these cells to escape normal apoptotic regulation [42].
Early in the disease, a mixed population of red cell precursors exists, but over
time, the hyper-responsive polycythemia vera clone increases and dominates,
exhibiting a survival advantage over that of the normal red cell precursors.
“Olympic polycythemia” describes the erythrocytosis associated with the
use of rHuEPO to boost hemoglobin concentrations in sports requiring major
cardiopulmonary output. Because rHuEPO differs from physiologic EPO at a
significant number of glycosylation sites, the exogenous rHuEPO can be
detected in the blood of these athletes [43]. (See Chapter 13 for further dis-
cussion.)
Other erythropoietic signaling pathways
The GATA-1 transcription factor expressed in erythroid precursors is essential
for their development and survival as it regulates the amounts of heme syn-
thetic enzymes, globin, membrane proteins, and other red cell components.
GATA-1 recognizes conserved DNA-GATA (guanine, adenine, thymine, ade-
nine) motifs in the promoter and/or enhancer regions of many erythroid-
expressed genes. Both EPO and GATA-1 strongly upregulate expression of the
anti-apoptotic gene bclX
L
, thus enhancing erythroblast survival [38, 39].
Angiotensin II (ATII) is well recognized as a regulator of renal hemody-
namics and blood pressure.
In vitro
studies have demonstrated that ATII can
stimulate the proliferation of BFU-E colonies in the presence of EPO [44]. The
ATII type-1 receptor (AT1R) has been identified on BFU-E-derived cells [45].
Whether ATII binding induces intracellular signaling by an independent or a
shared pathway with EPO is not clear. (In rat aortic smooth muscle cells, bind-
ing of ATII to its receptor initiates signaling through the JAK/STAT pathway
[46].) 10-20% of patients receiving a renal transplant develop erythrocytosis
although EPO concentrations may remain within the normal range. The
enhanced erythropoiesis can be controlled by the administration of
angiotensin-converting enzyme (ACE) inhibitors. ATII concentrations
decrease without reducing the amount of EPO. ACE inhibitors also have been
found to reduce the hematocrit in high altitude-associated polycythemia [47].
