Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Ningxia Medical University (The First People's Hospital of Yinchuan), Yinchuan 750001, China.
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan 750004, China.
Acta Biochim Biophys Sin (Shanghai). 2023 Jul 25;55(9):1456-1466. doi: 10.3724/abbs.2023127.
Homocysteine (Hcy) is a risk factor for multiple chronic diseases, and vascular endothelial cell injury has been regarded as the initiating step for this process. miRNAs are involved in Hcy-induced endothelial dysfunction, while the underlying mechanism and roles of miRNAs in pulmonary endothelial dysfunction induced by homocysteine are unknown. Here, we find that miR-205-5p alleviates pulmonary endothelial dysfunction by targeting FOXO1 in CBS mice to protect against Hcy-induced pulmonary endothelial dysfunction. Mechanistically, we show that Hcy can lead to DNA hypermethylation of the miR-205-5p promoter due to the increased binding of DNMT1 to its promoter, which contributes to reduction of miR-205-5p expression. In summary, miR-205-5p promoter hypermethylation causes downregulation of miR-205-5p expression, resulting in a reduction in miR-205-5p binding to FOXO1 during homocysteine-induced pulmonary endothelial dysfunction. Our data indicate that miR-205-5p may be a potential therapeutic target against Hcy-induced pulmonary injury.
同型半胱氨酸（Hcy）是多种慢性疾病的危险因素，血管内皮细胞损伤被认为是这一过程的起始步骤。miRNA 参与 Hcy 诱导的内皮功能障碍，而 miRNA 在 Hcy 诱导的肺血管内皮功能障碍中的潜在机制和作用尚不清楚。在这里，我们发现 miR-205-5p 通过靶向 CBS 小鼠中的 FOXO1 减轻肺内皮功能障碍，从而防止 Hcy 诱导的肺内皮功能障碍。在机制上，我们表明 Hcy 可以由于 DNMT1 与其启动子的结合增加而导致 miR-205-5p 启动子的 DNA 超甲基化，从而导致 miR-205-5p 表达减少。总之，miR-205-5p 启动子的超甲基化导致 miR-205-5p 表达下调，导致 Hcy 诱导的肺血管内皮功能障碍期间 miR-205-5p 与 FOXO1 的结合减少。我们的数据表明，miR-205-5p 可能是针对 Hcy 诱导的肺损伤的潜在治疗靶点。
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