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首页> 外文期刊>American Journal of Physiology >Cardiac ischemia-reperfusion injury induces ROS-dependent loss of PKA regulatory subunit RIalpha.
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Cardiac ischemia-reperfusion injury induces ROS-dependent loss of PKA regulatory subunit RIalpha.

机译：心脏缺血再灌注损伤诱导PKA调节亚基Rialpha的ROS依赖性损失。

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Type I PKA regulatory a-subunit (RIa; encoded by the Prkar1a gene) serves as the predominant inhibitor protein of the catalytic subunit of cAMP-dependent protein kinase (PKAc). However, recent evidence suggests that PKA signaling can be initiated by cAMP-independent events, especially within the context of cellular oxidative stress such as ischemia-reperfusion (I/R) injury. We determined whether RIa is actively involved in the regulation of PKA activity via reactive oxygen species (ROS)-dependent mechanisms during I/R stress in the heart. Induction of ex vivo global I/R injury in mouse hearts selectively downregulated RIa protein expression, whereas RII subunit expression appears to remain unaltered. Cardiac myocyte cell culture models were used to determine that oxidant stimulus (i.e., H2O2) alone is sufficient to induce RIa protein downregulation. Transient increase of RIa expression (via adenoviral overexpression) negatively affects cell survival and function upon oxidative stress as measured by increased induction of apoptosis and decreased mitochondrial respiration. Furthermore, analysis of mitochondrial subcellular fractions in heart tissue showed that PKA-associated proteins are enriched in subsarcolemmal mitochondria (SSM) fractions and that loss of RIa is most pronounced at SSM upon I/R injury. These data were supported via electron microscopy in A-kinase anchoring protein 1 (AKAP1)-knockout mice, where loss of AKAP1 expression leads to aberrant mitochondrial morphology manifested in SSM but not interfibrillar mitochondria. Thus, we conclude that modification of RIa via ROS-dependent mechanisms induced by I/R injury has the potential to sensitize PKA signaling in the cell without the direct use of the canonical cAMP-dependent activation pathway. NEW & NOTEWORTHY We uncovered a previously undescribed phenomenon involving oxidation-induced activation of PKA signaling in the progression of cardiac ischemia-reperfusion injury. Type I PKA regulatory subunit RIa, but not type II PKA regulatory subunits, is dynamically regulated by oxidative stress to trigger the activation of the catalytic subunit of PKA in cardiac myocytes. This effect may play a critical role in the regulation of subsarcolemmal mitochondria function upon the induction of ischemic injury in the heart.
机译：I型PKA调节A-亚基（RIA;由PRKAR1A基因编码）用作营养依赖性蛋白激酶（PKAC）的催化亚基的主要抑制剂蛋白。然而，最近的证据表明，PKA信号传导可以通过营养不实的事件开始，特别是在细胞氧化应激之如缺血再灌注（I / R）损伤的范围内。我们确定RIA在心脏中I / R应激期间通过反应性氧物种（ROS）依赖性机制是否积极参与PKA活性的调节。诱导小鼠心脏的exvivo全球I / R损伤有选择地下调RIA蛋白表达，而RII亚基表达似乎保持不变。使用心肌细胞细胞培养模型用于确定氧化剂刺激（即，H 2 O 2）足以诱导RIA蛋白的下调。 RIA表达（通过腺病毒过度表达）的瞬时增加对细胞存活率产生负面影响，并通过增加诱导细胞凋亡和降低线粒体呼吸来测量的氧化应激。此外，心脏组织中的线粒体亚细胞分数分析表明，PKA相关蛋白质富集在子半容物线粒体（SSM）级分中，并且在I / R损伤时，SSM最明显的RIA损失。通过电子显微镜通过A-激酶锚固蛋白1（akap1） - knockout小鼠的电子显微镜支持这些数据，其中Akap1表达的丧失导致异常的线粒体形态，表现为SSM但不是interfibrillar线粒体。因此，我们得出结论，通过I / R损伤诱导的ROS依赖机制对RIA的修饰具有潜在的致敏PKA信号传导在细胞中，而不直接使用规范阵营依赖性活化途径。新的和值得注意的是我们发现了先前未描述的现象，涉及心脏缺血再灌注损伤进展中的氧化诱导的PKA信号传导激活。 I型PKA调节亚基RIA，但不是II型PKA调节亚基，通过氧化应激动态调节，以引发心肌细胞中PKA催化亚基的激活。这种效果可能在诱导心脏缺血损伤时对次级思汞线粒体功能的调节作用。

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