Department of Obstetrics, Affiliated Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, Guangdong 518028, P.R. China.
Department of Emergency, Shenzhen Children's Hospital, Shenzhen, Guangdong 518026, P.R. China.
Mol Med Rep. 2020 Sep;22(3):1847-1858. doi: 10.3892/mmr.2020.11269. Epub 2020 Jun 23.
Preeclampsia (PE) is a complication during pregnancy that is diagnosed by a new onset of hypertension and proteinuria. Although the pathogenesis of PE is not fully understood, a growing body of evidence indicates that oxidative stress and mitochondrial dysfunction might contribute to the progression of PE. Therefore, the aim of the present study was to determine the role of mitophagy in mitochondrial dysfunction and oxidative stress in PE, and to evaluate the role of DNA damage‑regulated autophagy modulator 1 (DRAM1) in the development of PE. First, a mouse model of PE induced by hypoxia‑inducible factor 1α was established, and high levels of oxidative stress, apoptosis and mitochondrial dysfunction were found in the placentas of PE mice. Additionally, the placentas of PE mice exhibited decreased mitophagy and significantly decreased DRAM1 expression. To further explore the role of DRAM1 in mitophagy, DRAM1 was overexpressed in the placental tissues of PE mice, and this overexpression effectively improved the symptoms of PE mice and significantly reduced blood lipid and urine protein levels. DRAM1 overexpression also improved mitochondrial function and reduced oxidative stress in the placentas of PE mice. In addition, the overexpression of DRAM1 improved mitochondrial fusion and fission, and enhanced mitophagy. Altogether, these results indicated a key role for DRAM1 in mitophagy that contributed to the regulation of PE. To the best of the authors' knowledge, the present study provided the first evidence of a role for DRAM1 in PE, and offered novel insight into the pathophysiological mechanisms of PE.
子痫前期（PE）是一种妊娠并发症，通过新发生的高血压和蛋白尿来诊断。虽然 PE 的发病机制尚未完全阐明，但越来越多的证据表明，氧化应激和线粒体功能障碍可能导致 PE 的进展。因此，本研究旨在确定自噬在 PE 中的线粒体功能障碍和氧化应激中的作用，并评估 DNA 损伤调控自噬调节剂 1（DRAM1）在 PE 发展中的作用。首先，建立了缺氧诱导因子 1α诱导的 PE 小鼠模型，发现 PE 小鼠的胎盘存在高水平的氧化应激、细胞凋亡和线粒体功能障碍。此外，PE 小鼠的胎盘表现出减少的自噬和明显降低的 DRAM1 表达。为了进一步探讨 DRAM1 在自噬中的作用，在 PE 小鼠的胎盘组织中转染了 DRAM1，过表达 DRAM1 有效改善了 PE 小鼠的症状，并显著降低了血脂和尿蛋白水平。DRAM1 的过表达还改善了 PE 小鼠胎盘的线粒体功能并减少了氧化应激。此外，DRAM1 的过表达改善了线粒体融合和裂变，并增强了自噬。综上所述，这些结果表明 DRAM1 在自噬中的关键作用有助于调节 PE。据作者所知，本研究首次提供了 DRAM1 在 PE 中的作用的证据，并为 PE 的病理生理机制提供了新的见解。
