| HIF-1α/NLRP3信号通路在右美托咪定减轻心肌缺血再灌注致脑损伤中的作用 |
| 投稿时间：2025-07-15 修订日期：2025-07-31 点此下载全文 |
| 引用本文：程虎,程逍,李雪燕,亚力·亚森,戴晓雯,王江.HIF-1α/NLRP3信号通路在右美托咪定减轻心肌缺血再灌注致脑损伤中的作用[J].医学研究杂志,2025,54(12):93-98, 200 |
| DOI：
10.11969/j.issn.1673-548X.2025.12.016 |
| 摘要点击次数: 24 |
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| 基金项目:新疆维吾尔自治区卫生健康委员会青年医学科技人才项目(WJWY-202459)；新疆维吾尔自治区神经系统疾病研究重点实验室课题(XJDX1711-2435) |
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| 中文摘要:目的 评价缺氧诱导因子-1α(hypoxia-inducible factor-1α, HIF-1α)/NOD样受体相关蛋白3(NOD-like receptor pyrin domain-containing 3, NLRP3)信号通路在右美托咪定(dexmedetomidine, DEX)减轻心肌缺血再灌注(ischemia-reperfusion, I/R)致脑损伤中的作用。方法 选取30只SPF级雄性C57BL/6小鼠,体质量20～30g,8～10周龄。采用随机数字表法将其分为5组:假手术组(Sham组)、I/R组、I/R+DEX组(I/R-D组)、I/R+DEX+HIF-1抑制剂组(IR-DM组)、I/R+DEX+HIF-1抑制剂+NLRP3抑制剂组(I/R-DMC组),每组各6只。采用开胸手术结扎冠状动脉左前降支,缺血45min后松开结扎线结,再灌注24h,建立心肌I/R模型。于再灌注24h时采用Morris水迷宫实验评估小鼠的认知功能,行为学检测结束后留取小鼠动脉血标本,酶联免疫吸附试验(enzyme-linked immunoadsordent assay, ELISA)法检测血清神经损伤标志物水平。处死小鼠,分离脑组织。采用苏木精-伊红(hematoxylin-eosin, HE)染色观察海马组织病理变化,TUNEL法检测细胞凋亡率,免疫荧光染色法检测NLRP3的荧光强度,ELISA法检测炎性细胞因子水平,Western blot法检测HIF-1α/NLRP3信号通路关键蛋白(HIF-1α、ASC、IL-1β、NLRP3、cleaved caspase-1)的表达。结果 与Sham组比较,I/R组小鼠Morris水迷宫潜伏期显著延长,穿越平台次数及目标象限停留时间减少,神经损伤标志物水平升高,海马区病理损伤加重,炎性细胞因子水平、脑含水量及凋亡指数升高,NLRP3荧光强度增加,闭合蛋白(Occludin)表达下调,HIF-1α、ASC、IL-1β、NLRP3、cleaved caspase-1蛋白表达上调。与I/R组比较,I/R-D组Morris水迷宫潜伏期缩短,穿越平台次数及目标象限停留时间增加,神经损伤标志物水平降低,海马区病理损伤减轻,炎性细胞因子水平、脑含水量及凋亡指数降低,NLRP3荧光强度减弱,Occludin、HIF-1α蛋白表达上调,NLRP3、ASC、IL-1β、cleaved caspase-1蛋白表达下调。与I/R-D组比较,I/R-DM组Morris水迷宫潜伏期延长,穿越平台次数及目标象限停留时间减少,神经损伤标志物水平上升,海马区病理损伤加重,炎性细胞因子水平、脑含水量及凋亡指数升高,NLRP3荧光强度增加,Occludin、HIF-1α蛋白表达下降,NLRP3、ASC、IL-1β、cleaved caspase-1蛋白表达增加。与I/R-DM组比较,I/R-DMC组行为学结果明显改善,神经损伤标志物、炎性细胞因子水平、脑含水量及凋亡指数均降低,海马区病理损伤减轻,NLRP3荧光强度降低,Occludin蛋白表达上调,NLRP3、ASC、IL-1β、cleaved caspase-1蛋白表达下调,HIF-1α蛋白表达比较,差异无统计学意义。结论 DEX能够减轻心肌I/R所致脑损伤,这种保护机制的发挥与激活与HIF-1α/NLRP3信号通路相关。 |
| 中文关键词:右美托咪定 心肌缺血再灌注 脑损伤 缺氧诱导因子-1α NOD样受体相关蛋白3 |
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| Role of the HIF-1α/NLRP3 Signaling Pathway in Dexmedetomidine-mediated Attenuation of Myocardial Ischemia-reperfusion-induced Brain Injury. |
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| Abstract:Objective To evaluate the role of the hypoxia-inducible factor-1α (HIF-1α)/NOD-like receptor pyrin domain-containing 3 (NLRP3) signaling pathway in dexmedetomidine (DEX)-attenuated brain injury induced by myocardial ischemia-reperfusion (I/R). Methods Thirty SPF-grade male C57BL/6mice were selected, with a body weight of 20-30g, and an age of 8-10 weeks. They were randomly divided into 5groups using a random number table:Sham group, I/R group, I/R+DEX group (I/R-D group), I/R+DEX+HIF-1inhibitor group (I/R-DM group), and I/R+DEX+HIF-1 inhibitor+NLRP3 inhibitor group (I/R-DMC group), with 6 rats in each group. The left anterior descending coronary artery was ligated by thoracotomy, the ligated knot was released after 45min ischemia, then reperfusion was performed for 24h to establish a myocardial I/R model. At 24h of reperfusion, cognitive function was assessed by Morris water maze test. After behavioral testing, arterial blood samples were collected, and the levels of serum neural injury markers were measured by enzyme-linked immunoadsordent assay (ELISA). The mice were euthanized, and brain tissue were isolated. The pathological changes of hippocampal tissues were observed by hematoxylin-eosin (HE) staining; cellular apoptosis rate was detected via TUNEL assay; the fluorescence intensity of NLRP3 was detected by immunofluorescence staining; the levels of inflammatory cytokine were detected by ELISA; the expression of key proteins (HIF-1α, ASC, IL-1β, NLRP3, cleaved caspase-1) in HIF-1α/NLRP3signaling pathway were detected by Western blot. Results Compared with the Sham group, the I/R group showed prolonged Morris water maze latency, fewer platform crossings and less time in the target quadrant, elevated neural injury markers, more severe hippocampal pathological damage, increased inflammatory factors levels, increased brain water content and apoptosis index, enhanced NLRP3 fluorescence intensity, downregulated Occludin protein expression, and upregulated HIF-1α, ASC, IL-1β, NLRP3 and cleaved caspase-1 protein expressions. Compared with the I/R group, the I/R-D group showed shortened Morris water maze latency, more platform crossings and longer time in the target quadrant, reduced neural injury markers, alleviated hippocampal pathological damage, decreased inflammation factors levels, decreased brain water content and apoptosis index, weakened NLRP3 fluorescence intensity, upregulated Occludin and HIF-1α protein expressions, and downregulated NLRP3, ASC, IL-1β and cleaved caspase-1 protein expressions. Compared with the I/R-D group, the I/R-DM group showed prolonged Morris water maze latency, fewer platform crossings and less time in the target quadrant, elevated neural injury markers, aggravated hippocampal pathological damage, increased inflammation factors levels, increased brain water content and apoptosis index, enhanced NLRP3 fluorescence intensity, downregulated Occludin and HIF-1α protein expressions, and upregulated NLRP3, ASC, IL-1β and cleaved caspase-1 protein expressions. Compared with the I/R-DM group, the I/R-DMC group had improved behavioral outcomes, reduced neural injury markers and inflammation factors levels, decreased brain water content and apoptosis index, alleviated hippocampal pathological damage, weakened NLRP3 fluorescence intensity, upregulated Occludin protein expression, downregulated NLRP3, ASC, IL-1β and cleaved caspase-1 protein expressions, with no significant difference in HIF-1α protein expression. Conclusion DEX can mitigate myocardial I/R-induced brain injury. The exertion and activation of this protective mechanism are associated with the HIF-1α/NLRP3signaling pathway. |
| keywords:Dexmedetomidine Myocardial ischemia-reperfusion Brain injury Hypoxia-inducible factor-1α NOD-like receptor pyrin domain-containing 3 |
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