Medical Scientist Training Program, University of Pittsburgh School of Medicine, 15261, Pittsburgh, PA, USA.
Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, 15261, Pittsburgh, PA, USA.
Function (Oxf). 2022 Feb 17;3(2):zqac005. doi: 10.1093/function/zqac005. eCollection 2022.
Sickle cell disease (SCD) is a genetic red blood cell disorder characterized by increased reactive oxygen species (ROS) and a concordant reduction in antioxidant capacity in the endothelium. Superoxide dismutase 2 (SOD2) is a mitochondrial-localized enzyme that catalyzes the dismutation of superoxide to hydrogen peroxide. Decreased peripheral blood expression of SOD2 is correlated with increased hemolysis and cardiomyopathy in SCD. Here, we report for the first time that endothelial cells exhibit reduced SOD2 protein expression in the pulmonary endothelium of SCD patients. To investigate the impact of decreased SOD2 expression in the endothelium, SOD2 was knocked down in human pulmonary microvascular endothelial cells (hPMVECs). We found that SOD2 deficiency in hPMVECs results in endothelial cell dysfunction, including reduced cellular adhesion, diminished migration, integrin protein dysregulation, and disruption of permeability. Furthermore, we uncover that SOD2 mediates changes in endothelial cell function via processing of fibronectin through its inability to facilitate dimerization. These results demonstrate that endothelial cells are deficient in SOD2 expression in SCD patients and suggest a novel pathway for SOD2 in regulating fibronectin processing.
镰状细胞病（SCD）是一种遗传性红细胞疾病，其特征是活性氧（ROS）增加，内皮细胞的抗氧化能力相应降低。超氧化物歧化酶 2（SOD2）是一种定位于线粒体的酶，可催化超氧化物歧化为过氧化氢。外周血 SOD2 表达减少与 SCD 中的溶血和心肌病增加相关。在这里，我们首次报道 SCD 患者的肺内皮细胞中 SOD2 蛋白表达减少。为了研究内皮细胞中 SOD2 表达减少的影响，我们在人肺微血管内皮细胞（hPMVECs）中敲低了 SOD2。我们发现 hPMVECs 中的 SOD2 缺乏会导致内皮细胞功能障碍，包括细胞黏附减少、迁移减少、整合素蛋白失调以及通透性破坏。此外，我们发现 SOD2 通过其不能促进二聚化来处理纤维连接蛋白，从而介导内皮细胞功能的变化。这些结果表明，SCD 患者的内皮细胞中 SOD2 表达减少，并提示 SOD2 通过调节纤维连接蛋白处理的新途径。
