Impairment of AMPK-α2 augments detrusor contractions in bladder ischemia.
Impairment of AMPK-α2 augments detrusor contractions in bladder ischemia.
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DOI：
10.4111/icu.20210095
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发表时间：
2021-09
影响因子：
2.3
通讯作者：
Azadzoi KM
中科院分区：
文献类型：
--
作者：
Yang JH;Niu W;Li Y;Azadzoi KM
局部缺血破坏细胞能量稳态。腺苷一磷酸活化蛋白激酶α 2（AMPK-α2）是AMPK的一个亚基，可感知细胞能量剥夺并发出代谢应激信号。本研究旨在探讨AMPK-α2在膀胱缺血中的表达水平及其功能作用。采用球囊导管剥脱大鼠髂动脉内皮，造成载脂蛋白E基因敲除大鼠髂动脉粥样硬化和膀胱缺血。8周后，通过蛋白质印迹法分析总AMPK-α 2表达和磷酸化AMPK-α2表达。通过液相色谱串联质谱法（LC-MS/MS）评估AMPK-α2蛋白的结构完整性。通过用AMPK激活剂5-氨基咪唑-4-甲酰胺-1-β-D呋喃核糖苷（AICAR）处理动物来检查AMPK-α2的功能作用。在器官浴中测量组织收缩性，并通过免疫染色检查膀胱神经密度。膀胱缺血时AMPK-α2表达增加，磷酸化AMPK-α2表达下调。LC-MS/MS表明AMPK-α2功能结构域的翻译后修饰，包括磷酸化位点，表明催化失活的AMPK-α2在膀胱缺血中积累。用AICAR治疗大鼠减少了逼尿肌过度活动的收缩力，增加了膀胱容量，但对膀胱收缩的频率没有显着影响。AICAR减少了器官浴中缺血组织的收缩反应，并防止了膀胱缺血中神经纤维的丢失。缺血诱导AMPK-α2蛋白的翻译后修饰AMPK-α2的损伤可能与膀胱缺血时逼尿肌过度收缩和神经纤维丢失有关。AMPK激活剂可能对膀胱缺血引起的逼尿肌过度活动和神经退行性变具有治疗潜力。
Ischemia disrupts cellular energy homeostasis. Adenosine monophosphate-activated protein kinase alpha-2 (AMPK-α2) is a subunit of AMPK that senses cellular energy deprivation and signals metabolic stress. Our goal was to examine the expression levels and functional role of AMPK-α2 in bladder ischemia. Iliac artery atherosclerosis and bladder ischemia were engendered in apolipoprotein E knockout rats by partial arterial endothelial denudation using a balloon catheter. After eight weeks, total and phosphorylated AMPK-α2 expression was analyzed by western blotting. Structural integrity of AMPK-α2 protein was assessed by Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). Functional role of AMPK-α2 was examined by treating animals with the AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-D ribofuranoside (AICAR). Tissue contractility was measured in the organ bath and bladder nerve density was examined by immunostaining. Total AMPK-α2 expression increased in bladder ischemia, while phosphorylated AMPK-α2 was significantly downregulated. LC-MS/MS suggested post-translational modification of AMPK-α2 functional domains including phosphorylation sites, suggesting accumulation of catalytically inactive AMPK-α2 in bladder ischemia. Treatment of rats with AICAR diminished the force of overactive detrusor contractions and increased bladder capacity but did not have a significant effect on the frequency of bladder contractions. AICAR diminished contractile reactivity of ischemic tissues in the organ bath and prevented loss of nerve fibers in bladder ischemia. Ischemia induces post-translational modification of AMPK-α2 protein. Impairment of AMPK-α2 may contribute to overactive detrusor contractions and loss of nerve fibers in bladder ischemia. AMPK activators may have therapeutic potential against detrusor overactivity and neurodegeneration in bladder conditions involving ischemia.
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DOI：
10.1038/jcbfm.2009.255
发表时间：
2010-03
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
通讯作者：
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影响因子：
4.5
作者：
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通讯作者：
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DOI：
10.1073/pnas.252625599
发表时间：
2002-12-10
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
6.6
作者：
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通讯作者：
Azadzoi, Kazem M.
影响因子：
4.5
作者：
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