| ObjectivesHypoxic adaptation has been shown to exert beneficial effects on hearts subjected subsequent to ischemia/reperfusion injury. Intermittent hypoxic adaptation is so new a hypoxia pattern that its mechanisms for cardioprotective effects are unclear till now, especially in the aged. We therefore established a rat model of chronic intermittent hypoxia to investigate the effects of chronic intermittent hypoxic on myocardium and its cardioprotective effects on myocardial ischemia/reperfusion injury. The aim of this study is to investigate the protection by intermittent hypoxia against ischemia/reperfusion injury and to provide the theoretical and experimental evidence of prevention / treatment of clinical hypoxic/ischemic disease.Methods70 young adult rats and 70 aged rats were divided into two groups: intermittent hypoxia group and intermittent hypoxia+ischemia/reperfusion group. Both of these groups were subdivided into control group, IH1d, IH7d, IH14d and IH28d. Samples of intermittent hypoxia group were obtained at 1d,7d,14d,28d after intermittent hypoxia. The changes of right ventricular systolic pressure(RVSP),hypertrophy index of right ventricle,capillary density,SOD activity,MDA content and HIF-1,VEGF,Bcl-2 expression in myocardium were observed;The changes of pathology, SOD activity, MDA content, HIF-1,VEGF,Bcl-2 expression and apoptosis in myocardium following ischemia/reperfusion were also observed. The infiltration number of PMNs in myocardium was observed too.Results1.In intermittent hypoxia group, right ventricular systolic pressure(RVSP),hypertrophy index of right ventricle,capillary density and index of capillary/myocyte increased gradually and apparently at 28d. In contrast to young groups,angiogenesis of the aged group declined。2.The levels of HIF-1mRNA and VEGFmRNA of myocardium at 4h after intermittent hypoxia increased gradually and peaked at IH7~14d, until IH28d they also remained high levels. In contrast to young groups,the expression of HIF-1,VEGF in aged group declined after intermittent hypoxia。3.The expression of Bcl-2 increased apparently at 4h after intermittent hypoxia and peaked at IH7~14d, until IH28h it also remained high level. Apoptotic index(AI)increased gradually and apparently at 28d. The expression of Bcl-2 and apoptotic index increased significantly in aged group.4.In intermittent hypoxia group, SOD activity in myocardium increased gradually and MDA activity decreased.5.Apoptotic index and the infiltration number of PMNs increased after the period of reperfusion in the group control. Intermittent hypoxic adaptation was effective in reducing the infiltration number of PMNs and apoptotic index. At the same time,the infarct size/ischemia area at risk of groups IH1d-28d after ischemia/reperfusion were smaller than those of group control. 6. The expression of HIF-1 and VEGF in IH groups was significantly higher than group control after ischemia/reperfusion. HIF-1 in the aged group was lower than that of group young. 7.The expression of Bcl-2 in IH groups increased significantly after ischemia/ reperfusion. Compared with the aged group, Bcl-2 in group young did not show significant difference. 8. Compared to that of control, SOD in IH groups increased significantly and MDA decreased significantly after ischemia/reperfusion. Conclusion1.Chronic intermittent hypoxia induces the angiogenesis in myocardium by up-regulation of HIF-1 and VEGF. Hypoxia-inducible factor 1 (HIF-1) may mediate adaptive responses to hypoxia/ischemia.2. Up-regulation of Bcl-2 in myocardium during intermittent hypoxia and ischemia/ reperfusion relates to reduction of myocardial cell apoptosis. 3. Chronic intermittent hypoxic adaptation strengthens antioxidative ability of myocardium. 4. Intermittent hypoxic adaptation offers protective effects on myocardial injuries. It seems likely that attenuation of infarct size,cardiomyocyte apoptosis and the infiltration number of PMNs is involved in the protective mechanisms of adaptation to chronic int... |
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