Erythropoietin (EPO) is a member of the class I family of cytokines
with a strong ability to stimulate erythropoiesis. The endogenous
EPO is mainly synthesized and secreted by the kidney,
and the recombinant EPO is utilized in patients suffering from
different kinds of anemia. EPO influences erythropoiesis
by binding to its specific receptor which is expressed on the
surface of immature erythroblasts. However, several studies
have demonstrated that EPO and EPO receptors are not only
expressed in erythroblasts but also in a number of cell types
including those within the cardiovascular and nervous system,
suggesting that the effects of EPO extend beyond regulation of
erythropoiesis. There are different kinds of EPO, namely, epoetin
alfa, epoetin beta, and epoetin gamma, which are analogues
of recombinant human EPO (rhEPO) derived from a cloned human
erythropoietin gene. All of them have the same 165 amino
acid sequence with a molecular weight of 30,400 daltons and
have the same pharmacological actions as native EPO. The
normal serum concentrations of EPO for individuals with normal
hematocrit range from 4-27 mU/mL. However, in certain
conditions of anemia and hypoxia, EPO levels can be increased
100-1000 times the normal serum EPO concentration.
Moreover, the subcutaneous administration of a single 600 U/
kg dose of epoetin alfa to healthy volunteers produced a peak
serum concentration of over 1000 mU/mL after 24 hours.
A second generation drug, namely, darbepoetin has a threefold
longer circulating half-life than rhEPO. It was shown that darbepoetin
alfa is 3.6-fold more potent than rhEPO in increasing the
hematocrit when each is administered thrice weekly, but when
the administration frequency is reduced to once weekly, darbepoetin
alfa is approximately 13-fold higher in vivo potency than
rhEPO. A third-generation EPO-related molecule called
continuous EPO receptor activator (CERA) has been manufac
tured. The elimination half-life of CERA in humans is considerably
increased to about 130 hours maintaining a stable control
of hemoglobin levels with a monthly interval dose. The
tissue protective effects of EPO, beyond the hematopoietic system,
is mediated by activation of homodimeric EPO receptor,
but is also believed to be mediated by its actions on the heterotrimeric
complex consisting of EPO receptor and the β-common
receptor. Nitric oxide (NO) is a potent vasodilator formed in
endothelial cells, and plays a key role in control of the cardiovascular
system. It was shown that EPO can exert non-erythropoietic
effects in vascular endothelium and is increasingly
regarded as a potent tissue protective cytokine. Several studies
demonstrated that EPO decreases tissue damage by inhibition
of apoptosis and reduction of inflammatory cytokines.
In-vitro treatment with low dose of rhEPO increased endothelial
nitric oxide synthase (eNOS) protein expression in cultured
endothelial cells. On the other hand, incubation of human
coronary artery endothelial cells with high dose of rhEPO
for 24 hours inhibited eNOS expression and NO production suggesting
that high dose of EPO may have detrimental effects on
endothelial function.
EPO has a vast variety of cardiovascular effects. It exerts its effects
on cardiac as well as the vascular tissues since EPO receptors
are expressed in cardiomyocytes, vascular endothelial cells
and smooth muscle cells. The clinical dosage required
to observe EPO-induced tissue protection is much higher than
that required for hematopoietic effects. There is robust
experimental evidence of beneficial effects with the use
of EPO in the cardiovascular system. However, all the plausible
mechanisms should be tested in clinical situations to properly
evaluate clinical outcomes. There are some adverse events
data described in clinical trials in patients with heart failure, kidney disease, myocardial infarction, and stroke. The
adverse side effects associated with EPO therapy were due to
its pleiotropic effects mainly in the cardiovascular system including
hypertension, thrombosis and augmented tumor angiogenesis. Single-center studies have shown that EPO
therapy of anemia in patients with heart failure was associated
with improvement in exercise capacity, improved cardiac and
renal function and reduced use of diuretics. Other trials
evaluated the safety and efficacy of darbepoetin alfa at a
dosage of 0.75μg/kg once every 2 weeks in symptomatic heart
failure patients. It was demonstrated that the incidence
of adverse events in these trials was similar between placeboand
darbepoetin alfa-treated patients. However, the significant
increase in hemoglobin shown with darbepoetin alfa
therapy correlated well with improved health-related quality
of life.
The results from pre-clinical studies attribute multiple
mechanisms of protection by EPO against myocardial disorders
besides anemia treatment. Treatment with EPO may decrease
apoptosis of myocytes, induce neovascularization by promoting
myocardial angiogenesis increasing collateral vessels, reduce
collagen deposition in ischemic myocardium, as well as,
improve left ventricular function. However, large clinical trials
did not demonstrate those benefits. Similarly, trials in
patients with anemia and heart failure did not demonstrate improved
clinical outcomes and raise concerns about increased
complications [25, 26]. It is highly possible that EPO may have
failed in these clinical trials because of the employment of insufficient
dose. Preclinical studies have frequently used doses
in the range of 1,000 to 5,000 IU/kg, while just a dose of 300 IU/
kg were utilized in many large clinical trials. Although this lower
dose is adequate for the EPO receptors in the erythroblasts, the
EPO receptors found on multiple cell types responsible for cardiovascular
protection are different. However, the explanation
may not be that simple. There is a complex interplay
between vascular abnormalities and inflammatory mediators.
There are several different cell types involved, and, within each
individual cell, there are complex interactions among multiple
signaling pathways. On the other hand, the use of higher doses
of EPO in those large clinical trials might have had developed
adverse effects such as thrombosis and hypertension.
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