Erythropoietin, but Not Asialoerythropoietin or Carbamyl-Erythropoietin, Attenuates Monocrotaline-Induced Pulmonary Hypertension in Rats

Abstract

Erythropoietin (EPO) has long been utilized for the treatment of renal anemia. The erythropoietin receptor (EPOR) is also expressed in the cardiovascular and central nervous systems in addition to an erythroid lineage, to provide an organoprotective role against several types of cellular stress. Pulmonary hypertension (PH) is a poor prognostic disease caused by primary and secondary pulmonary vascular injury. We observed the effects of EPO derivatives on monocrotaline-induced PH in rats on the supposition that EPO may protect small arteries from injury. Asialoerythropoietin (AEPO) lacks sialic acids in the termini of carbohydrate chains that results in rapid clearance from blood. Carbamyl-erythropoietin (CEPO) interacts with EPOR/βc heterodimers, but not with EPOR homodimers expressed in erythroid cells. Monocrotaline-injected rats were treated with continuous intravenous injection of 2500 ng/kg/day of EPO, AEPO, or CEPO for 21 days, and lung histology, cardiac function, and mRNA expression in the lungs were examined. Wall thickening of small arteries in the lungs and PH were improved by administration of EPO, but not by its non-hematopoietic derivatives, AEPO, or CEPO. Erythropoietin administration increased mRNA expression of the anti-apoptotic molecule, Bcl-xL, and maintained expression of the CD31 antigen. We conclude that lungs may express EPOR homoreceptors, but not heteroreceptors. Adequate serum erythropoietin levels may be essential for pulmonary protective effects.

• pulmonary hypertension
• monocrotaline
• erythropoietin
• asialoerythropoietin
• carbamyl-erythropoietin

ACKNOWLEDGMENTS

The authors disclosed the acceptance of the following financial support for the research and/or authorship of this article: Grants-in-Aid for scientific research from The Ministry of Education in Japan (grant numbers 21590887, 19590856, and 17590714 to K.T.; 21590888 to T.O.; and 18590806 to K.K.).

Declaration of interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.