Premium
Darbepoetin‐mediated cardioprotection after myocardial infarction involves multiple mechanisms independent of erythropoietin receptor–common β‐chain heteroreceptor
Author(s) -
Kanellakis Peter,
Pomilio Giovanna,
Agrotis Alex,
Gao Xiaoming,
Du XiaoJun,
Curtis David,
Bobik Alexander
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00876.x
Subject(s) - erythropoietin receptor , medicine , erythropoietin , endocrinology , cardiac function curve , fibrosis , pharmacology , heart failure
BACKGROUND AND PURPOSE Darbepoetin, a long‐acting erythropoietin derivative, attenuates cardiomyocyte apoptosis and improves short‐term (3 days) cardiac function, but the mechanisms responsible are unknown. We investigated potential mechanisms by which darbepoetin exerts cardioprotection following myocardial infarction in mice and the significance of the erythropoietin receptor (EPOR)–common β‐chain (c‐β‐chain) heteroreceptor. EXPERIMENTAL APPROACH Mice underwent 60 min coronary occlusion followed by treatment with vehicle or a single dose of darbepoetin. Effects on gene expression, apoptosis and neutrophil accumulation in infarcted left ventricle were assessed 24 h later. Cardiac function, effects on vascularization and fibrosis were assessed 28 days later. The significance of EPOR–c‐β‐chain heteroreceptor was examined 28 days after infarction using mice deficient in c‐β‐chain. KEY RESULTS Twenty‐four hours after darbepoetin, mRNAs encoding haeme oxygenase‐1 (HO‐1), iNOS and brain natriuretic peptide (BNP) were markedly elevated only in infarcted regions, and the frequency of apoptotic cells attenuated. Inflammation was also attenuated with reductions in neutrophil numbers. Darbepoetin also elevated mRNAs encoding angiogenic factors: placental growth factor, monocyte chemoattractant protein‐1 and interleukin‐1β. Twenty‐eight days after treatment, CD31+ vessels in the infarct zone doubled and fibrosis reduced. Cardiac haemodynamics were improved. Darbepoetin also improved cardiac haemodynamics in c‐β‐chain‐deficient mice, increased HO‐1 and iNOS expression and vessel numbers and attenuated fibrosis. CONCLUSIONS AND IMPLICATIONS Darbepoetin stimulates expression of haeme oxygenase, iNOS, BNP and angiogenic factors specifically in infarcted left ventricle that attenuates inflammation, apoptosis and fibrosis; elevate vessel numbers; and improve cardiac function. The EPOR–c‐β‐chain heteroreceptor is not essential for these effects.