Warenits Alexandra-Maria, Hatami Jasmin, Müllebner Andrea, Ettl Florian, Teubenbacher Ursula, Magnet Ingrid Anna Maria, Bauder Barbara, Janata Andreas, Miller Ingrid, Moldzio Rudolf, Kramer Anne-Margarethe, Sterz Fritz, Holzer Michael, Högler Sandra, Weihs Wolfgang, Duvigneau Johanna Catharina
Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria.
Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria.
Front Med (Lausanne). 2020 Sep 10;7:513. doi: 10.3389/fmed.2020.00513. eCollection 2020.
Heme oxygenase (HO) and biliverdin reductase (BVR) activities are important for neuronal function and redox homeostasis. Resuscitation from cardiac arrest (CA) frequently results in neuronal injury and delayed neurodegeneration that typically affect vulnerable brain regions, primarily hippocampus (Hc) and motor cortex (mC), but occasionally also striatum and cerebellum. We questioned whether these delayed effects are associated with changes of the HO/BVR system. We therefore analyzed the activities of HO and BVR in the brain regions Hc, mC, striatum and cerebellum of rats subjected to ventricular fibrillation CA (6 min or 8 min) after 2 weeks following resuscitation, or sham operation. From all investigated regions, only Hc and mC showed significantly decreased HO activities, while BVR activity was not affected. In order to find an explanation for the changed HO activity, we analyzed protein abundance and mRNA expression levels of HO-1, the inducible, and HO-2, the constitutively expressed isoform, in the affected regions. In both regions we found a tendency for a decreased immunoreactivity of HO-2 using immunoblots and immunohistochemistry. Additionally, we investigated the histological appearance and the expression of markers indicative for activation of microglia [ (TNFR1) mRNA and immunoreactivity for ionized calcium-binding adapter molecule 1 (Iba1])], and activation of astrocytes [immunoreactivity for glial fibrillary acidic protein (GFAP)] in Hc and mC. Morphological changes were detected only in Hc displaying loss of neurons in the cornu ammonis 1 () region, which was most pronounced in the 8 min CA group. In this region also markers indicating inflammation and activation of pro-death pathways (expression of HO-1 and TNFR1 mRNA, as well as Iba1 and GFAP immunoreactivity) were upregulated. Since HO products are relevant for maintaining neuronal function, our data suggest that neurodegenerative processes following CA may be associated with a decreased capacity to convert heme into HO products in particularly vulnerable brain regions.
血红素加氧酶（HO）和胆绿素还原酶（BVR）的活性对于神经元功能和氧化还原稳态至关重要。心脏骤停（CA）复苏后常导致神经元损伤和延迟性神经变性，通常影响易损脑区，主要是海马体（Hc）和运动皮层（mC），但偶尔也会影响纹状体和小脑。我们质疑这些延迟效应是否与HO/BVR系统的变化有关。因此，我们分析了复苏后2周接受室颤性CA（6分钟或8分钟）的大鼠或假手术大鼠的脑区Hc、mC、纹状体和小脑中HO和BVR的活性。在所有研究区域中，只有Hc和mC的HO活性显著降低，而BVR活性未受影响。为了解释HO活性的变化，我们分析了受影响区域中诱导型HO-1和组成型表达的异构体HO-2的蛋白质丰度和mRNA表达水平。在这两个区域，我们通过免疫印迹和免疫组织化学发现HO-2的免疫反应性有降低的趋势。此外，我们研究了Hc和mC中指示小胶质细胞激活的组织学外观和标记物表达[（TNFR1）mRNA和离子钙结合衔接分子1（Iba1）的免疫反应性]，以及星形胶质细胞激活的标记物表达[胶质纤维酸性蛋白（GFAP）的免疫反应性]。仅在Hc检测到形态学变化，表现为海马1区（）神经元丢失，在8分钟CA组最为明显。在该区域，指示炎症和促死亡途径激活的标记物（HO-1和TNFR1 mRNA的表达以及Iba1和GFAP的免疫反应性）也上调。由于HO产物与维持神经元功能相关，我们的数据表明，CA后的神经退行性过程可能与特别易损脑区将血红素转化为HO产物的能力降低有关。
