Vascular Biology & Atherosclerosis, BakerIDI Heart and Diabetes Institute, Melbourne, Australia.
Br J Pharmacol. 2010 Aug;160(8):2085-96. doi: 10.1111/j.1476-5381.2010.00876.x.
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 beta-chain (c-beta-chain) heteroreceptor.
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-beta-chain heteroreceptor was examined 28 days after infarction using mice deficient in c-beta-chain.
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-1beta. 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-beta-chain-deficient mice, increased HO-1 and iNOS expression and vessel numbers and attenuated fibrosis.
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-beta-chain heteroreceptor is not essential for these effects.
达贝泊汀是一种长效促红细胞生成素衍生物，可减轻心肌细胞凋亡并改善短期（3 天）心功能，但具体机制尚不清楚。我们研究了达贝泊汀在小鼠心肌梗死后发挥心脏保护作用的潜在机制，以及促红细胞生成素受体（EPOR）-共同β链（c-β链）异源受体的意义。
小鼠行 60 分钟冠状动脉闭塞，再给予载体或单次达贝泊汀治疗。24 小时后评估梗死左心室基因表达、凋亡和中性粒细胞浸润的变化。28 天后评估心功能、血管生成和纤维化的变化。28 天后，通过缺乏 c-β链的小鼠检测 EPOR-c-β链异源受体的意义。
达贝泊汀治疗 24 小时后，仅在梗死区域显著上调血红素加氧酶-1（HO-1）、诱导型一氧化氮合酶（iNOS）和脑钠肽（BNP）的 mRNA，凋亡细胞的频率降低。炎症也减轻，中性粒细胞数量减少。达贝泊汀还上调了血管生成因子的 mRNA：胎盘生长因子、单核细胞趋化蛋白-1 和白细胞介素-1β。治疗 28 天后，梗死区 CD31+血管数增加一倍，纤维化减少。心功能得到改善。达贝泊汀还改善了 c-β链缺陷型小鼠的心功能，增加了 HO-1 和 iNOS 的表达、血管数量，并减轻了纤维化。
达贝泊汀可特异性刺激梗死左心室血红素加氧酶、iNOS、BNP 和血管生成因子的表达，减轻炎症、凋亡和纤维化；增加血管数量；改善心功能。EPOR-c-β链异源受体不是这些作用所必需的。
