1. Erythropoietin (EPO) Essentials Erin Drumheller, BSN SRNA York College of Pennsylvania

2. Objectives Describe the physiology of EPO and the EPO-R Describe the physiology of EPO and the EPO-R Briefly discuss the role of EPO in erythropoiesis Briefly discuss the role of EPO in erythropoiesis Identify some of the non-hematopoietic functions of EPO Identify some of the non-hematopoietic functions of EPO Discuss the significance of EPO to the anesthetist Discuss the significance of EPO to the anesthetist

3. EPO Hematopoietic glycoprotein Hematopoietic glycoprotein 30 kDa, 165 Amino Acids 30 kDa, 165 Amino Acids 4 glycans 4 glycans 3 N-glycans and 1 O-glycan 3 N-glycans and 1 O-glycan Produced in peritubular fibroblasts of the kidney Produced in peritubular fibroblasts of the kidney Production controlled at transcriptional level Production controlled at transcriptional level (Patnaik & Tefferi, 2009)

4. EPOR Cytokine Class I Receptor Cytokine Class I Receptor JAK JAK Homodimeric and Heterodimeric Homodimeric and Heterodimeric Activates numerous pathways Activates numerous pathways Expressed in CFU-E stage, not on mature RBC Expressed in CFU-E stage, not on mature RBC Expressed in other prevalent tissues Expressed in other prevalent tissues (Chateauvieux, et al., 2011)

5. EPO Production Occurs at the transcriptional level Occurs at the transcriptional level Hypoxia Inducible Factors (HIF) Hypoxia Inducible Factors (HIF) HIF-2α (sensing) and HIF-β (binding) HIF-2α (sensing) and HIF-β (binding) Promoter and Repressor (HRE & GATA2) Promoter and Repressor (HRE & GATA2)

6. (Patnaik & Tefferi, 2009)

7. (Jelkmann, 2013)

8. (Chateauvieux, et al., 2011)

9. Non-hematopoietic Functions http://biol4550jj.blogspot.com/2012_11_01_arcive.html

10. (Wang, et al., 2014)

12. Anesthesia Implications Can EPO protect the brain in hypoxic environments? Can EPO protect the brain in hypoxic environments? Noguchi, et al.; Sautina, et al. Noguchi, et al.; Sautina, et al. (Noguchi, et al., 2007)

13. Volatile Anesthetics & Locals

14. Nouette-Gaulain, et al., 2011)

15. rhEPO Administration Hypertension Hypertension Venous Thromboembolism Venous Thromboembolism Mortality Mortality Cost Cost

16. Questions?

17. References Asahara, T. & Kawamoto, A. (2004). Endothelial progenitor cells for postnatal vasculogenesis. American Journal of Physiology: Cell Physiology, 287 (3), 572-579. DOI: 10/1152/ajpcell.00330.2003 Asahara, T. & Kawamoto, A. (2004). Endothelial progenitor cells for postnatal vasculogenesis. American Journal of Physiology: Cell Physiology, 287 (3), 572-579. DOI: 10/1152/ajpcell.00330.2003 Beleslin-Cokic, B. B., Cokic, V., Yu, X., Weksler, B., Schechter, A. N. & Noguchi, C. T. (2004). Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood, 104(7), 2073-2080. DOI 10.1182/blood-2004-02-0744 Beleslin-Cokic, B. B., Cokic, V., Yu, X., Weksler, B., Schechter, A. N. & Noguchi, C. T. (2004). Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood, 104(7), 2073-2080. DOI 10.1182/blood-2004-02-0744 Chateauvieux, S., Grigorakaki, C., Morceau, F., Dicato, M. & Diederich, M. (2011). Erythropoietin, erythropoiesis and beyond. Biochemical Pharmacology, 82, 1291-1303. DOI 10.1016/j.bcp.2011.06.04 Chateauvieux, S., Grigorakaki, C., Morceau, F., Dicato, M. & Diederich, M. (2011). Erythropoietin, erythropoiesis and beyond. Biochemical Pharmacology, 82, 1291-1303. DOI 10.1016/j.bcp.2011.06.04 Jelkmann, W. (2011). Regulation of erythropoietin production. Journal of Physiology, 589(6), 1251- 1258. DOI 10.1113/jphysiol.2010.195057 Jelkmann, W. (2011). Regulation of erythropoietin production. Journal of Physiology, 589(6), 1251- 1258. DOI 10.1113/jphysiol.2010.195057 Jelkmann, W. (2013). Physiology and pharmacology of erythropoietin. Transfusion Medicine and Hemotherapy, 40, 302-309. DOI 10.1159/000356193 Jelkmann, W. (2013). Physiology and pharmacology of erythropoietin. Transfusion Medicine and Hemotherapy, 40, 302-309. DOI 10.1159/000356193 Khurana, I. (2014). Medical physiology for undergraduate students. Philadelphia, PA: Elsevier. Khurana, I. (2014). Medical physiology for undergraduate students. Philadelphia, PA: Elsevier. Noguchi, C. T., Asavaritikrai, P., Teng, R & Jia, Y. (2007). Role of erythropoietin in the brain. Critical Reviews in Oncology Hematology, 64, 159-171. DOI 10.1016/j.critrevonc.2007.03.001 Noguchi, C. T., Asavaritikrai, P., Teng, R & Jia, Y. (2007). Role of erythropoietin in the brain. Critical Reviews in Oncology Hematology, 64, 159-171. DOI 10.1016/j.critrevonc.2007.03.001

18. References Nouette-Gaulain, K., Bellance, N., Prévost, B., Passerieux, E., Pertuiset, C., Galbes, O., … & Sztark, F. (2009). Erythropoietin protects against local anesthetic myotoxicity during continuous regional analgesia. Anesthesiology, 10(3), 648-659. Nouette-Gaulain, K., Bellance, N., Prévost, B., Passerieux, E., Pertuiset, C., Galbes, O., … & Sztark, F. (2009). Erythropoietin protects against local anesthetic myotoxicity during continuous regional analgesia. Anesthesiology, 10(3), 648-659. Patnaik, M. M. & Tefferi, A. (2009). The complete evaluation of erythrocytosis: congenital and acquired. Leukemia, 23, 834-844. DOI: 20150420132334296156764 Patnaik, M. M. & Tefferi, A. (2009). The complete evaluation of erythrocytosis: congenital and acquired. Leukemia, 23, 834-844. DOI: 20150420132334296156764 Sautina, L., Sautin, Y., Beem, E., Zhou, Z., Schuler, A., Brennan, J., … & Segal, M. (2010). Induction of nitric oxide by erythropoietin is mediated by the  common receptor and requires interaction with VEGF receptor 2. Blood, 115(4), 896-905. DOI 10.1182/blood-2009-04- 216432201504201328221454976201 Sautina, L., Sautin, Y., Beem, E., Zhou, Z., Schuler, A., Brennan, J., … & Segal, M. (2010). Induction of nitric oxide by erythropoietin is mediated by the  common receptor and requires interaction with VEGF receptor 2. Blood, 115(4), 896-905. DOI 10.1182/blood-2009-04- 216432201504201328221454976201 Tanaka, T., Kai, S., Koyama, T., Daijo, H., Adachi, T., Fukuda, K. & Hirota, K. (2011). General anesthetics inhibit erythropoietin induction under hypoxic conditions in the mouse brain. PLoS ONE, 6(12). Tanaka, T., Kai, S., Koyama, T., Daijo, H., Adachi, T., Fukuda, K. & Hirota, K. (2011). General anesthetics inhibit erythropoietin induction under hypoxic conditions in the mouse brain. PLoS ONE, 6(12). Trincavelli, M. L., Da Pozzo, E., Ciampi, O., Cuboni, S., Daniele, S., Abbracchio, M. P. & Martini, C. (2013). Regulation of erythropoietin receptor activity in endothelial cells by different erythropoietin (EPO) derivatives: An in vitro study. International Journal of Molecular Sciences, 14, 2258-2281. DOI 10.3390/ijms14022258 Trincavelli, M. L., Da Pozzo, E., Ciampi, O., Cuboni, S., Daniele, S., Abbracchio, M. P. & Martini, C. (2013). Regulation of erythropoietin receptor activity in endothelial cells by different erythropoietin (EPO) derivatives: An in vitro study. International Journal of Molecular Sciences, 14, 2258-2281. DOI 10.3390/ijms14022258 Wang, L., Di, L. & Noguchi, C. T. (2014). Erythropoietin, a novel versatile player regulating energy metabolism beyond the erythroid system. International Journal of Biological Sciences, 10, 921- 939. DOI 10.7150/ijbs.9518 Wang, L., Di, L. & Noguchi, C. T. (2014). Erythropoietin, a novel versatile player regulating energy metabolism beyond the erythroid system. International Journal of Biological Sciences, 10, 921- 939. DOI 10.7150/ijbs.9518