HIF-P4H-2 deficiency protects against skeletal muscle ischemia-reperfusion injury
HIF-P4H-2 deficiency protects against skeletal muscle ischemia-reperfusion injury
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DOI：
10.1007/s00109-015-1349-0
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发表时间：
2016-03-01
影响因子：
4.7
通讯作者：
Koivunen, Peppi
中科院分区：
文献类型：
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作者：
Karsikas, Sara;Myllymaki, Mikko;Koivunen, Peppi
我们在这里表明，小鼠低氧诱导因子脯氨酰4-羟化酶-2（HIF-P4 H-2）（HIF-P4 h-2（gt/gt）），HIF α亚基稳定性的主要调节因子，在其骨骼肌中具有低氧稳定性的HIF-1 α和HIF-2 α。在Hif-p4 h-2（gt/gt）小鼠的骨骼肌中，毛细血管的大小增加，而不是它们的数量增加，而糖原的量减少。糖酵解酶，糖原分支酶1和单羧酸转运蛋白4的基因的表达水平增加，在HIF-p4 h-2（gt/gt）骨骼肌，而没有显着增加检测到的任何血管影响因素的水平研究。运动后，Hif-p4 h2（gt/gt）小鼠的血清乳酸水平比野生型小鼠恢复得更快。Hif-p4 h-2（gt/gt）小鼠肝脏磷酸烯醇式丙酮酸羧激酶活性升高，这可能导致乳酸清除更快。Hif-p4 h-2（gt/gt）小鼠肢体缺血再灌注损伤后梗死面积较小。毛细血管直径的增加与梗死面积的减少相关。缺血再灌注后，Hif-p4 h-2（gt/gt）小鼠骨骼肌糖原含量、ATP/ADP和CrP/Cr水平均高于野生型小鼠。糖原含量的增加与磷酸果糖激酶信使RNA（mRNA）表达的增加以及ATP/ADP和CrP/Cr水平的增加相关，提示HIF-P4 H-2缺陷支持缺血-再灌注期间的能量代谢和对损伤的保护。关键信息HIF-P4 H-2缺陷保护骨骼肌免受缺血-再灌注损伤。涉及的机制是通过常氧HIF-1 α和HIF-1 α介导的。HIF-P4 H-2缺乏增加毛细血管的大小，但不增加数量。
We show here that mice hypomorphic for hypoxia-inducible factor prolyl 4-hydroxylase-2 (HIF-P4H-2) (Hif-p4h-2(gt/gt)), the main regulator of the stability of the HIF alpha subunits, have normoxic stabilization of HIF-1 alpha and HIF-2 alpha in their skeletal muscles. The size of the capillaries, but not their number, was increased in the skeletal muscles of the Hif-p4h-2(gt/gt) mice, whereas the amount of glycogen was reduced. The expression levels of genes for glycolytic enzymes, glycogen branching enzyme 1 and monocarboxylate transporter 4, were increased in the Hif-p4h-2(gt/gt) skeletal muscles, whereas no significant increases were detected in the levels of any vasculature-influencing factor studied. Serum lactate levels of the Hif-p4h2(gt/gt) mice recovered faster than those of the wild type following exercise. The Hif-p4h-2(gt/gt) mice had elevated hepatic phosphoenolpyruvate carboxykinase activity, which may have contributed to the faster clearance of lactate. The Hif-p4h-2(gt/gt) mice had smaller infarct size following limb ischemia-reperfusion injury. The increased capillary size correlated with the reduced infarct size. Following ischemia-reperfusion, glycogen content and ATP/ADP and CrP/Cr levels of the skeletal muscle of the Hif-p4h-2(gt/gt) mice were higher than in the wild type. The higher glycogen content correlated with increased expression of phosphofructokinase messenger RNA (mRNA) and the increased ATP/ADP and CrP/Cr levels with reduced apoptosis, suggesting that HIF-P4H-2 deficiency supported energy metabolism during ischemia-reperfusion and protection against injury.Key messagesHIF-P4H-2 deficiency protects skeletal muscle from ischemia-reperfusion injury.The mechanisms involved are mediated via normoxic HIF-1 alpha and HIF-2 alpha stabilization.HIF-P4H-2 deficiency increases capillary size but not number.HIF-P4H-2 deficiency maintains energy metabolism during ischemia-reperfusion.