Alteration in erythropoietin-induced cardioprotective signaling by postinfarct ventricular remodeling
Alteration in erythropoietin-induced cardioprotective signaling by postinfarct ventricular remodeling
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DOI：
10.1124/jpet.105.095745
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发表时间：
2006-04-01
影响因子：
3.5
通讯作者：
Shimamoto, K
中科院分区：
文献类型：
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作者：
Miki, T;Miura, T;Shimamoto, K
梗死后重构损害缺血预处理机制。我们研究心肌对促红细胞生成素（EPO）受体激活的反应是否被梗死后重构所改变。心肌梗死后冠脉结扎组（post-MI）或假手术组（sham）诱导心肌梗死4周后，分离大鼠心脏，进行25 min全身缺血/ 2 h再灌注。梗死面积表示为排除瘢痕性梗死的危险区域（即左心室）的百分比（% I/ R）。心肌梗死后心脏重量增加15%，但血浆EPO水平和心肌EPO受体水平没有组间差异。EPO输注（5 U/ ml）显著降低了% I/ R，在假手术中从59.9 +/- 4.1降至36.2 +/- 4.2，在心肌梗死后从58.1 +/- 5.0降至35.2 +/- 4.0。这种EPO诱导的保护作用对磷脂酰肌醇3-激酶（PI3K）抑制剂2-(4- morpholinyl)- 8- phenyl- 4H- 1- benzopyran- 4- one LY294002敏感。然而，LY294002和wortmannin都没有抑制EPO诱导的心肌梗死后的保护作用，EPO对Janus激酶2的磷酸化减弱，Akt的磷酸化在心肌梗死后未被检测到。一种冠酰环化酶抑制剂1H-[1,2,4]恶二唑[4,3- A]喹诺伐林- 1- 1，一种线粒体ATP敏感K（+）通道（mitoK ATP通道）阻滞剂5-羟基乙酸酯，心肌梗死后，细胞因子信号抑制因子(SOCS)- 1蛋白水平比假手术组高50%，但SOCS- 3水平相似。这些发现表明，梗死后重构可能通过增加SOCS- 1破坏EPO受体到PI3K的细胞信号传导。然而，在重构心肌中，EPO受体激活PI3K/ Akt的缺失似乎可以通过冠酰环化酶- mitok （ATP）通道途径上游的机制来补偿，从而实现EPO诱导的保护。
Postinfarct remodeling impairs mechanisms of ischemic preconditioning. We examined whether myocardial response to activation of the erythropoietin ( EPO) receptor is modified by postinfarct remodeling. Four weeks after induction of myocardial infarction ( MI) by coronary ligation in post- MI group ( post-MI) or a sham operation in sham group ( sham), rat hearts were isolated and subjected to 25- min global ischemia/ 2- h reperfusion. Infarct size was expressed as a percentage of risk area ( i. e., left ventricle) from which scarred infarct was excluded (% I/ R). The heart weight was 15% larger in post- MI, but there was no intergroup difference in plasma EPO levels or myocardial EPO receptor levels. EPO infusion ( 5 U/ ml) significantly reduced % I/ R from 59.9 +/- 4.1 to 36.2 +/- 4.2 in sham and from 58.1 +/- 5.0 to 35.2 +/- 4.0 in post- MI. This EPO- induced protection was sensitive to a phosphatidylinositol 3- kinase ( PI3K) inhibitor, 2-( 4- morpholinyl)- 8- phenyl- 4H- 1- benzopyran- 4- one LY294002), in sham. However, neither LY294002 nor wortmannin inhibited the EPO- induced protection in post- MI. Phosphorylation of Janus kinase 2 by EPO was attenuated and phosphorylation of Akt was not detected in post- MI. A guanylyl cyclase inhibitor, 1H-[ 1,2,4] oxadiazole[ 4,3- a] quinoxalin- 1- one, and a mitochondrial ATP- sensitive K (+) channel ( mitoK ATP channel) blocker, 5- hydroxydecanoate, inhibited EPO- induced protection in both sham and post- MI. Suppressor of cytokine signaling ( SOCS)- 1 protein level was higher by 50% in post- MI than in sham, although SOCS- 3 levels were similar. These findings suggest that postinfarct remodeling disrupts cellular signaling from the EPO receptor to PI3K, presumably by increased SOCS- 1. However, in the remodeled myocardium, lack of PI3K/ Akt activation by the EPO receptor seems to be compensated by a mechanism upstream of the guanylyl cyclase-mitoK(ATP) channel pathway to achieve EPO- induced protection.