Abstract
Background: Chronic heart failure (CHF) patients are frequently anaemic despite elevated endogenous erythropoietin (Epo) levels. We tested the hypothesis that this might be due to Epo resistance and investigated whether any defects apparent were due to Epo receptor (EpoR) downregulation and/or impaired Epo-induced signal transduction. Methods: We studied 28 CHF patients (age 64 ± 10 yrs, LVEF 29 ± 9%, 89% male) and 12 healthy controls (65 ± 11 yrs, 75% male). Circulating erythroid progenitors (BFU-E) were cultured with 0, 1, 3 and 9 U/mL Epo. Circulating erythroblast surface EpoR and intracellular phosphorylated Signal Transducer and Activator of Transcription (phosphoSTAT)-5 expression were determined by flow cytometry. Results: Whilst BFU-E from control and non-anaemic subjects required only 3 U/mL Epo to significantly increase their numbers from baseline (1 U/mL), those from anaemic patients required 9 U/mL Epo. Lower Epo sensitivities related to higher interleukin-6 (r = - 0.41, P = 0.01) and soluble tumour necrosis factor receptor 2 (r = - 0.38, P = 0.02) levels. EpoR-positive cells were more abundant in anaemic patients (P <0.001). Although erythroblasts from anaemic patients exhibited higher baseline EpoR and phosphoSTAT5 expression (all P <0.05), Epo stimulation triggered significant increases in phosphoSTAT5 levels only in erythroblasts from control subjects and not in those from anaemic patients. Conclusion: The responsiveness of erythroid cells to Epo is diminished in anaemic CHF patients. This is not due to EpoR downregulation but relates to a profound blunting of Epo-induced JAK-STAT signalling. Whilst residual Epo sensitivity can be exploited clinically with erythropoietic agents, targeting the mechanisms underlying Epo resistance in CHF may provide greater efficacy.
| Original language | English |
|---|---|
| Pages (from-to) | 359-364 |
| Number of pages | 6 |
| Journal | International Journal of Cardiology |
| Volume | 164 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Apr 15 2013 |
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Keywords
- Anaemia
- Erythropoietin resistance
- Heart failure
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
Cite this
Erythropoietin resistance contributes to anaemia in chronic heart failure and relates to aberrant JAK-STAT signal transduction. / Okonko, Darlington O.; Marley, Stephen B.; Anker, Stefan D.; Poole-Wilson, Philip A.; Gordon, Myrtle Y.
In: International Journal of Cardiology, Vol. 164, No. 3, 15.04.2013, p. 359-364.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Erythropoietin resistance contributes to anaemia in chronic heart failure and relates to aberrant JAK-STAT signal transduction
AU - Okonko, Darlington O.
AU - Marley, Stephen B.
AU - Anker, Stefan D.
AU - Poole-Wilson, Philip A.
AU - Gordon, Myrtle Y.
PY - 2013/4/15
Y1 - 2013/4/15
N2 - Background: Chronic heart failure (CHF) patients are frequently anaemic despite elevated endogenous erythropoietin (Epo) levels. We tested the hypothesis that this might be due to Epo resistance and investigated whether any defects apparent were due to Epo receptor (EpoR) downregulation and/or impaired Epo-induced signal transduction. Methods: We studied 28 CHF patients (age 64 ± 10 yrs, LVEF 29 ± 9%, 89% male) and 12 healthy controls (65 ± 11 yrs, 75% male). Circulating erythroid progenitors (BFU-E) were cultured with 0, 1, 3 and 9 U/mL Epo. Circulating erythroblast surface EpoR and intracellular phosphorylated Signal Transducer and Activator of Transcription (phosphoSTAT)-5 expression were determined by flow cytometry. Results: Whilst BFU-E from control and non-anaemic subjects required only 3 U/mL Epo to significantly increase their numbers from baseline (1 U/mL), those from anaemic patients required 9 U/mL Epo. Lower Epo sensitivities related to higher interleukin-6 (r = - 0.41, P = 0.01) and soluble tumour necrosis factor receptor 2 (r = - 0.38, P = 0.02) levels. EpoR-positive cells were more abundant in anaemic patients (P <0.001). Although erythroblasts from anaemic patients exhibited higher baseline EpoR and phosphoSTAT5 expression (all P <0.05), Epo stimulation triggered significant increases in phosphoSTAT5 levels only in erythroblasts from control subjects and not in those from anaemic patients. Conclusion: The responsiveness of erythroid cells to Epo is diminished in anaemic CHF patients. This is not due to EpoR downregulation but relates to a profound blunting of Epo-induced JAK-STAT signalling. Whilst residual Epo sensitivity can be exploited clinically with erythropoietic agents, targeting the mechanisms underlying Epo resistance in CHF may provide greater efficacy.
AB - Background: Chronic heart failure (CHF) patients are frequently anaemic despite elevated endogenous erythropoietin (Epo) levels. We tested the hypothesis that this might be due to Epo resistance and investigated whether any defects apparent were due to Epo receptor (EpoR) downregulation and/or impaired Epo-induced signal transduction. Methods: We studied 28 CHF patients (age 64 ± 10 yrs, LVEF 29 ± 9%, 89% male) and 12 healthy controls (65 ± 11 yrs, 75% male). Circulating erythroid progenitors (BFU-E) were cultured with 0, 1, 3 and 9 U/mL Epo. Circulating erythroblast surface EpoR and intracellular phosphorylated Signal Transducer and Activator of Transcription (phosphoSTAT)-5 expression were determined by flow cytometry. Results: Whilst BFU-E from control and non-anaemic subjects required only 3 U/mL Epo to significantly increase their numbers from baseline (1 U/mL), those from anaemic patients required 9 U/mL Epo. Lower Epo sensitivities related to higher interleukin-6 (r = - 0.41, P = 0.01) and soluble tumour necrosis factor receptor 2 (r = - 0.38, P = 0.02) levels. EpoR-positive cells were more abundant in anaemic patients (P <0.001). Although erythroblasts from anaemic patients exhibited higher baseline EpoR and phosphoSTAT5 expression (all P <0.05), Epo stimulation triggered significant increases in phosphoSTAT5 levels only in erythroblasts from control subjects and not in those from anaemic patients. Conclusion: The responsiveness of erythroid cells to Epo is diminished in anaemic CHF patients. This is not due to EpoR downregulation but relates to a profound blunting of Epo-induced JAK-STAT signalling. Whilst residual Epo sensitivity can be exploited clinically with erythropoietic agents, targeting the mechanisms underlying Epo resistance in CHF may provide greater efficacy.
KW - Anaemia
KW - Erythropoietin resistance
KW - Heart failure
UR - http://www.scopus.com/inward/record.url?scp=84884213329&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84884213329&partnerID=8YFLogxK
U2 - 10.1016/j.ijcard.2011.07.045
DO - 10.1016/j.ijcard.2011.07.045
M3 - Article
C2 - 21821297
AN - SCOPUS:84884213329
VL - 164
SP - 359
EP - 364
JO - International Journal of Cardiology
JF - International Journal of Cardiology
SN - 0167-5273
IS - 3
ER -