Abstract
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 (mitoKATP 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-mitoKATP channel pathway to achieve EPO-induced protection.
Footnotes
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This study was supported by a grant from Sapporo Medical University Academic Foundation, Sapporo, Japan; a grant from Northern Advancement Center for Science and Technology, Sapporo, Japan; and a grant from Chugai Pharmaceutical Co., Tokyo, Japan. This study was presented, in part, at Scientific Sessions 2005 of the American Heart Association, 2005 Nov 13–16; Dallas, TX.
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doi:10.1124/jpet.105.095745.
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ABBREVIATIONS: EPO, erythropoietin; IR, ischemia/reperfusion; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PC, ischemic preconditioning; mitoKATP channel, mitochondrial ATP-sensitive K+ channel; MI, myocardial infarction; LY294002, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; ODQ, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one; 5-HD, 5-hydroxydecanoate; SOCS, suppressor of cytokine signaling; JAK, Janus kinase; eNOS, endothelial nitric-oxide synthase; LVDP, left ventricular developed pressure; bpm, beats per minute; %I/R, infarct size as a percentage of risk area; ERK, extracellular signal-regulated kinase; TNF-α, tumor necrosis factor α; PKG, protein kinase G; HR, heart rate.
- Received September 16, 2005.
- Accepted December 22, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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