Department of Emergency, Ganzhou People's Hospital, Ganzhou, Jiangxi, China.
J Cell Mol Med. 2024 Nov;28(22):e70232. doi: 10.1111/jcmm.70232.
Sepsis is a life-threatening syndrome triggered by a cascade of dysregulated immune responses. Sepsis-induced myocardial injury (SIMI) substantially impacts the survival time of septic patients. However, the molecular mechanisms underlying the pathology of SIMI remain unclear. Immune-related differentially expressed genes in SIMI were identified through RNA sequencing and bioinformatics analysis. The expression levels of hub genes were detected using reverse transcription quantitative PCR. BMP10 was knocked down in the lipopolysaccharide-induced mouse and cardiac microvascular endothelial cell (CMEC) models, and its functions were assessed by a series of in vitro and in vivo assays. Cell adhesion and HIF-1 pathway-associated protein expressions were measured by western blot. Fenbendazole-d3 was used to investigate whether BMP10 influenced SIMI development by modulating the HIF-1 pathway. Six key genes were screened, of which BMP10, HAMP, TRIM5, and MLANA were highly expressed, and PTPRN2 and AVP were lowly expressed. BMP10 knockdown ameliorated histopathological changes and inhibited apoptosis and CMEC immune infiltration in SIMI. BMP10 knockdown reduced inflammatory factor (IL-6, MCP-1, IFN-β, and CCL11) levels and protein expressions of cell adhesion-related molecules (VCAM-1 and ICAM-1). Mechanistically, the HIF-1 pathway agonist, Fenbendazole-d3, significantly reversed the inhibitory effects of BMP10 knockdown on SIMI in vitro, indicating that BMP10 knockdown impeded the development of SIMI by suppressing the HIF-1α pathway. BMP10 knockdown blocks SIMI progression by inhibiting the HIF-1α pathway, which provides a new potential therapeutic strategy for SIMI treatment.
脓毒症是一种由免疫反应失调引发的危及生命的综合征。脓毒症诱导的心肌损伤（SIMI）极大地影响了脓毒症患者的生存时间。然而，SIMI 病理学的分子机制尚不清楚。通过 RNA 测序和生物信息学分析鉴定 SIMI 中的免疫相关差异表达基因。使用逆转录定量 PCR 检测关键基因的表达水平。在脂多糖诱导的小鼠和心脏微血管内皮细胞（CMEC）模型中敲低 BMP10，并通过一系列体外和体内实验评估其功能。通过 Western blot 测量细胞黏附和 HIF-1 通路相关蛋白的表达。芬苯达唑-d3 用于研究 BMP10 是否通过调节 HIF-1 通路影响 SIMI 的发展。筛选出 6 个关键基因，其中 BMP10、HAMP、TRIM5 和 MLANA 表达较高，而 PTPRN2 和 AVP 表达较低。BMP10 敲低改善了 SIMI 的组织病理学变化，抑制了凋亡和 CMEC 免疫浸润。BMP10 敲低降低了炎症因子（IL-6、MCP-1、IFN-β 和 CCL11）水平和细胞黏附相关分子（VCAM-1 和 ICAM-1）的蛋白表达。在机制上，HIF-1 通路激动剂芬苯达唑-d3 显著逆转了 BMP10 敲低对 SIMI 的体外抑制作用，表明 BMP10 敲低通过抑制 HIF-1α 通路阻碍了 SIMI 的发展。BMP10 敲低通过抑制 HIF-1α 通路阻止 SIMI 进展，为 SIMI 的治疗提供了一种新的潜在治疗策略。
