Zhao Ling, Li Shichao, Wang Xiaoyu, Zhang Lingyan, Zhang Jingge, Liu Xiyun, Hu Yuyan, Xian Xiaohui, Zhang Feng, Li Wenbin, Zhang Min
Department of Pathophysiology, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, People's Republic of China.
Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, Hebei Province, 050017, People's Republic of China.
J Inflamm Res. 2024 Oct 1;17:6935-6954. doi: 10.2147/JIR.S476458. eCollection 2024.
Obesity is recognized as a primary risk factor for cerebral ischemia, which has shown a significant increase in its incidence among obese patients. The exact mechanism by which obesity exacerbates cerebral ischemic injury is not fully understood though. The present study validated the hypothesis that obesity mediates pyroptosis by the AGEs/RAGE signaling pathway to exacerbate cerebral ischemic injury.
Leptin receptor knockout ( ) rats were used in this study to construct an obesity model, and the middle cerebral artery occlusion (MCAO) models of ischemic stroke were established in obese rats and their wild-type (WT) littermates respectively. Zea-Longa score, TTC and H&E staining were utilized to evaluate the neurological impairment. Western Blot, immunohistochemistry, and immunofluorescence were used to detect protein expressions. Transmission electron microscopy was used to observe the pores in the neuronal cell membrane in the ischemic penumbra cortex.
Compared with WT littermates, obese rats exhibited exacerbated neuronal injury after MCAO, with higher expressions of NLRP3 inflammasome and pyroptosis-related proteins in the cortical tissue of the penumbra. Moreover, more GSDMD pores were observed on the neuronal cell membranes of obese rats according to the electron microscopy. Inhibition of NLRP3 inflammasome expression with MCC950 inhibited neuronal pyroptosis after cerebral ischemia in obese rats, thus reducing neuronal injury. We also found that compared with WT littermates, the levels of AGEs and RAGE in the cortex of obese rats are significantly higher, with further increase after cerebral ischemia. Inhibition of AGEs/RAGE signaling pathway with FPS-ZM1 reduced the NLRP3 inflammasome-mediated neuronal pyroptosis in obese rats, thereby mitigating the neuronal damage after cerebral ischemia.
The AGEs/RAGE signaling pathway is involved in the exacerbation of cerebral ischemic injury in obese rats via regulating NLRP3-mediated neuronal pyroptosis.
肥胖被认为是脑缺血的主要危险因素，肥胖患者中其发病率显著增加。然而，肥胖加重脑缺血损伤的确切机制尚未完全明确。本研究验证了肥胖通过晚期糖基化终末产物（AGEs）/晚期糖基化终末产物受体（RAGE）信号通路介导细胞焦亡从而加重脑缺血损伤这一假说。
本研究采用瘦素受体敲除（ ）大鼠构建肥胖模型，并分别在肥胖大鼠及其野生型（WT）同窝仔鼠中建立缺血性脑卒中的大脑中动脉闭塞（MCAO）模型。采用Zea-Longa评分、TTC染色及苏木精-伊红（H&E）染色评估神经功能缺损。采用蛋白质免疫印迹法、免疫组织化学法及免疫荧光法检测蛋白表达。采用透射电子显微镜观察缺血半暗带皮质神经元细胞膜上的孔洞。
与WT同窝仔鼠相比，肥胖大鼠MCAO后神经元损伤加重，半暗带皮质组织中NLRP3炎性小体及细胞焦亡相关蛋白表达更高。此外，根据电子显微镜观察，肥胖大鼠神经元细胞膜上观察到更多的gasdermin D（GSDMD）孔洞。用MCC950抑制NLRP3炎性小体表达可抑制肥胖大鼠脑缺血后的神经元焦亡，从而减轻神经元损伤。我们还发现，与WT同窝仔鼠相比，肥胖大鼠皮质中AGEs和RAGE水平显著更高，脑缺血后进一步升高。用FPS-ZM1抑制AGEs/RAGE信号通路可减少肥胖大鼠中NLRP3炎性小体介导的神经元焦亡，从而减轻脑缺血后的神经元损伤。
AGEs/RAGE信号通路通过调节NLRP3介导的神经元焦亡参与肥胖大鼠脑缺血损伤的加重。
