NLRP3 inflammasome-mediated vascular EC pyroptosis is a key event in the pathogenesis of atherosclerosis. Dysregulation of glucose metabolism is involved in EC dysfunction. Although BDNF plays a protective role in vascular endothelium physiological activity, the mechanisms underlying this activity are not yet clear. In this study, we investigated the role of BDNF in NLRP3 inflammasome-mediated EC pyroptosis and its associated reprogramming of glucose metabolism. HUVECs were treated with human rBDNF under ox-LDL stimulation. rBDNF alleviated ox-LDL-induced NLRP3 inflammasome formation and HUVEC pyroptosis, as evaluated by NLRP3, caspase1-p10, interleukin-18, and interleukin-1β protein levels, co-localization of NLRP3 and apoptosis-associated speck-like protein, and lactate dehydrogenase release. These effects were prevented by tropomyosin receptor kinase B inhibition and KLF2 silencing. The hyper-activation of glycolysis induced by ox-LDL-induced was mitigated by rBDNF via KLF2 as assessed by glucose uptake, lactate production, and extracellular acidification rate. In addition, the BDNF/KLF2 pathway preserved the mitochondrial membrane potential, intracellular reactive oxygen species generation, electron transport chain processing, oxygen consumption rate, and adenosine triphosphate production. Furthermore, KLF2 interacted with HK1 and HK1 overexpression evoked NLRP3 inflammasome formation. At the clinical level, plasma BDNF and lactate levels were measured in 274 patients who underwent computed tomography and coronary angiography for CAD diagnosis. Patients with CAD had lower BDNF and increased lactate levels than those without CAD. In 94 patients with CAD, circulating BDNF levels were inversely associated with lactate levels. In the receiver operating characteristic analysis of CAD, the areas under the curves for 1/BDNF, lactate, and 1/BDNF+lactate were 0.707, 0.702, and 0.753 respectively. These results indicate that BDNF and lactate are linked in atherosclerotic patients, and BDNF inhibits ox-LDL induced NLRP3 inflammasome formation and pyroptosis in HUVECs via KLF2/HK1-mediated glucose metabolism modulation and mitochondrial homeostasis preservation.

NLRP3 炎症小体介导的血管内皮细胞焦亡是动脉粥样硬化发病机制中的关键事件。葡萄糖代谢失调与 EC 功能障碍有关。尽管 BDNF 在血管内皮生理活动中起保护作用，但这种活动的机制尚不清楚。在这项研究中，我们研究了 BDNF 在 NLRP3 炎症小体介导的 EC 细胞焦亡中的作用及其相关的葡萄糖代谢重编程。在 ox-LDL 刺激下用人 rBDNF 处理 HUVEC。rBDNF 减轻了 ox-LDL 诱导的 NLRP3 炎症小体形成和 HUVEC 细胞焦亡，如通过 NLRP3、caspase1-p10、白细胞介素-18 和白细胞介素-1β 蛋白水平、NLRP3 和凋亡相关斑点样蛋白的共定位以及乳酸所评估的脱氢酶释放。这些作用被原肌球蛋白受体激酶 B 抑制和 KLF2 沉默阻止。由 ox-LDL 诱导的糖酵解的过度激活被 rBDNF 通过 KLF2 减轻，如葡萄糖摄取、乳酸产生和细胞外酸化率所评估。此外，BDNF/KLF2 通路保留了线粒体膜电位、细胞内活性氧的产生、电子传递链加工、耗氧率和三磷酸腺苷的产生。此外，KLF2 与 HK1 和 HK1 过表达相互作用引起 NLRP3 炎性体形成。在临床水平上，在 274 名接受计算机断层扫描和冠状动脉造影以诊断 CAD 的患者中测量了血浆 BDNF 和乳酸水平。与没有 CAD 的患者相比，患有 CAD 的患者具有较低的 BDNF 和较高的乳酸水平。在 94 名 CAD 患者中，循环 BDNF 水平与乳酸水平呈负相关。在 CAD 的受试者工作特征分析中，1/BDNF、乳酸和 1/BDNF+乳酸的曲线下面积分别为 0.707、0.702 和 0.753。这些结果表明 BDNF 和乳酸在动脉粥样硬化患者中存在联系，并且 BDNF 通过 KLF2/HK1 介导的葡萄糖代谢调节和线粒体稳态保存抑制 HUVEC 中 ox-LDL 诱导的 NLRP3 炎性体形成和细胞焦亡。