Burger Dylan, Xiang Fuli, Hammoud Lamis, Lu Xiangru, Feng Qingping
Dept. of Physiology and Pharmacology, Univ. of Western Ontario, London, ON, Canada N6A 5C1.
Am J Physiol Heart Circ Physiol. 2009 Jan;296(1):H84-93. doi: 10.1152/ajpheart.00372.2008. Epub 2008 Nov 7.
We have recently demonstrated that erythropoietin (EPO) protects cardiomyocytes from apoptosis during myocardial ischemia-reperfusion (I/R). The objective of the present study was to investigate the role of heme oxygenase (HO)-1 in the antiapoptotic effects of EPO. Primary cultures of neonatal mouse cardiomyocytes were subjected to anoxia-reoxygenation (A/R). Pretreatment with EPO significantly reduced apoptosis in A/R-treated cells. This reduction in apoptosis was preceded by an increase in the mRNA and protein expression of HO-1. Selective inhibition of HO-1 using chromium mesoporphyrin (CrMP) significantly diminished the ability of EPO to inhibit apoptosis. Cotreatment of EPO with SB-202190, an inhibitor of p38 activation, blocked the EPO-mediated HO-1 expression and antiapoptotic effects, suggesting a p38-dependent mechanism. The in vivo significance of p38 and HO-1 as mediators of EPO's cardioprotection was investigated in mice subjected to myocardial I/R. Pretreatment with EPO decreased infarct size as well as I/R-induced apoptosis in wild-type mice. However, these effects were significantly diminished in HO-1(-/-) mice. Furthermore, EPO given during ischemia reduced infarct size in mice subjected to I/R, and this effect was blocked by CrMP treatment in wild-type mice. Moreover, inhibition of p38 diminished the cardioprotective effects of EPO. We conclude that upregulation of HO-1 expression via p38 signaling contributes to EPO-mediated cardioprotection during myocardial I/R.
我们最近证明，促红细胞生成素（EPO）可在心肌缺血再灌注（I/R）期间保护心肌细胞免于凋亡。本研究的目的是探讨血红素加氧酶（HO）-1在EPO抗凋亡作用中的作用。对新生小鼠心肌细胞原代培养物进行缺氧复氧（A/R）处理。EPO预处理显著降低了A/R处理细胞中的凋亡。这种凋亡的减少之前是HO-1的mRNA和蛋白表达增加。使用中卟啉铬（CrMP）选择性抑制HO-1显著削弱了EPO抑制凋亡的能力。EPO与p38激活抑制剂SB-202190共同处理可阻断EPO介导的HO-1表达和抗凋亡作用，提示存在p38依赖性机制。在经历心肌I/R的小鼠中研究了p38和HO-1作为EPO心脏保护介质的体内意义。EPO预处理可减小野生型小鼠的梗死面积以及I/R诱导的凋亡。然而，在HO-1基因敲除（-/-）小鼠中，这些作用显著减弱。此外，在缺血期间给予EPO可减小经历I/R小鼠的梗死面积，但在野生型小鼠中这种作用被CrMP处理所阻断。此外，抑制p38可减弱EPO的心脏保护作用。我们得出结论，通过p38信号上调HO-1表达有助于EPO在心肌I/R期间介导的心脏保护作用。
