Molecular characterization of brown adipose tissue in a ‘protoendothermic’ mammal provides a novel approach to the understanding of uncoupling protein evolution
Molecular characterization of brown adipose tissue in a ‘protoendothermic’ mammal provides a novel approach to the understanding of uncoupling protein evolution
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“原吸热”哺乳动物棕色脂肪组织的分子特征为理解解偶联蛋白质进化提供了一种新方法
DOI：
10.1016/j.bbabio.2012.06.125
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Meyer C.W.
中科院分区：
文献类型：
--
作者：
Oelkrug R;Goetze N;Exner C;Ganjam G.K;Müller S;Kutschke M;Tschöp M;Heldmaier G;Jastroch M;Meyer C.W.
解偶联蛋白(UCP)包括线粒体内膜阴离子载体的一个亚家族，它调节膜质子电导[1]。虽然它们的生理功能仍不确定，但广泛的证据表明，它们可以防止自由基的产生和氧化应激[1，2]。此外，缺氧可上调骨骼肌中的UCP3[3]，UCP2和UCP3都可能赋予心肌缺血耐受性[4]。由于在低氧条件下，活性氧物种(ROS)也会增加[5]，UCP3的增加可能代表了一种旨在减少这些条件下氧化损伤的机制。我们的目的是研究心脏停搏诱导的缺血对人心脏UCP2和UCP3表达水平的影响。心脏活检取自体外循环瓣膜置换术患者的左心室。分别于停搏液输注前、停跳液后20分钟或30分钟取材。定量聚合酶链式反应和免疫印迹法分别检测UCP2和UCP3的mRNA和蛋白表达水平。UCP3的表达(mRNA和蛋白)在缺血过程中增加，而UCP2的表达没有变化。缺血还诱导ATF-1(活性转录因子1)的磷酸化和抗氧化性转录因子Nrf2(NF-E2相关因子2)的核积聚。因此，几个Nrf2靶基因的mRNA水平也被诱导。相反，低氧诱导因子(HIF)敏感基因没有改变。缺血前后5种线粒体OXPHOS复合体的相对水平相似。皮尔逊相关系数显示UCP3与Nrf2呈正相关。心肌缺血时UCP3的上调可能代表了线粒体去极化的心肌保护机制，旨在限制ROS的产生。
Uncoupling proteins (UCPs) comprise a subfamily of mitochondrial inner membrane anion carriers that regulate the membrane proton conductance [1]. Although their physiological function is still not established, extensive evidence indicates that they protect against free radical production and oxidative stress [1, 2]. In addition, hypoxia upregulates UCP3 in skeletal muscle [3] and both UCP2 and UCP3 might confer cardiac ischemia tolerance [4]. Since reactive oxygen species (ROS) also increase during hypoxia [5], the increase in UCP3 could represent a mechanism aimed at decreasing oxidative damage in these conditions. Our aim was to study the effect of cardioplegic arrest-induced ischemia on the expression levels of UCP2 and UCP3 in the human heart. Cardiac biopsies from the left ventricle were obtained from patients undergoing valve replacement surgery with cardiopulmonary bypass. Biopsies were taken before and 20 or 30min after the infusion of cardioplegic solution. UCP2 and UCP3 mRNA and protein expression levels were determined by quantitative PCR and immunoblot, respectively. UCP3 expression (mRNA and protein) increased during ischemia whereas UCP2 remained unchanged. Ischemia also induced the phosphorylation of ATF-1 (active transcription factor 1) and the nuclear accumulation of the antioxidant transcription factor Nrf2 (NF-E2-related factor 2). Consequently, the mRNA levels of several Nrf2 target genes were also induced. On the contrary, HIF (hypoxia inducible factor) sensitive genes did not change. Relative levels of the five mitochondrial OXPHOS complexes were similar before and after ischemia. Pearson correlation coefficients indicated a positive correlation between UCP3 and Nrf2. The up-regulation of UCP3 during cardiac ischemia could represent a cardioprotective mechanism of mitochondrial depolarization aimed at limiting ROS production.