Division of Brain Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju-si, Chungcheongbuk-do, 28159, South Korea.
Division of Emerging Virus and Vector Research, Korea National Institute of Health, Korea Disease Control and Prevention Agency, Cheongju-si, Chungchengbuk-do, 28159, South Korea.
Biochem Biophys Res Commun. 2022 Oct 20;626:66-71. doi: 10.1016/j.bbrc.2022.07.113. Epub 2022 Aug 4.
Increasing evidence suggests incomplete recovery of COVID-19 patients, who continue to suffer from cardiovascular diseases, including cerebral vascular disorders (CVD) and neurological symptoms. Recent findings indicate that some of the damaging effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, especially in the brain, may be induced by the spike protein, leading to the disruption of the initial blood-brain barrier (BBB). SARS-CoV-2-infected cells and animals exhibit age-dependent pathogenesis. In this study, we identified endothelial BACE1 as a critical mediator of BBB disruption and cellular senescence induced by the SARS-CoV-2 spike S1 subunit protein. Increased BACE1 in human brain microvascular endothelial cells (HBMVEC) decreases the levels of tight junction proteins, including ZO-1, occludin, and claudins. Moreover, BACE1 overexpression leads to the accumulation of p16 and p21, typical hallmarks of cellular senescence. Our findings show that the SARS-CoV-2 spike S1 subunit protein upregulated BACE1 expression in HBMVECs, causing endothelial leakage. In addition, the SARS-CoV-2 spike S1 subunit protein induced p16 and p21 expression, indicating BACE1-mediated cellular senescence, confirmed by β-Gal staining in HBMVECs. In conclusion, this study demonstrated that BACE1-mediated endothelial cell damage and senescence may be linked to CVD after COVID-19 infection.
越来越多的证据表明，COVID-19 患者并未完全康复，他们仍继续遭受心血管疾病的困扰，包括脑血管疾病（CVD）和神经系统症状。最近的研究结果表明，严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染的一些破坏性影响，尤其是在大脑中，可能是由刺突蛋白引起的，导致初始血脑屏障（BBB）的破坏。SARS-CoV-2 感染的细胞和动物表现出与年龄相关的发病机制。在这项研究中，我们确定内皮细胞 BACE1 是由 SARS-CoV-2 刺突 S1 亚基蛋白引起的 BBB 破坏和细胞衰老的关键介质。人脑血管内皮细胞（HBMVEC）中 BACE1 的增加会降低紧密连接蛋白的水平，包括 ZO-1、occludin 和 claudins。此外，BACE1 的过表达导致 p16 和 p21 的积累，这是细胞衰老的典型标志。我们的研究结果表明，SARS-CoV-2 刺突 S1 亚基蛋白上调了 HBMVECs 中的 BACE1 表达，导致内皮细胞渗漏。此外，SARS-CoV-2 刺突 S1 亚基蛋白诱导了 p16 和 p21 的表达，表明 BACE1 介导的细胞衰老，这在 HBMVECs 的β-Gal 染色中得到了证实。总之，这项研究表明，BACE1 介导的内皮细胞损伤和衰老可能与 COVID-19 感染后的 CVD 有关。
