| 26 | 0 | 30 |
| 下载次数 | 被引频次 | 阅读次数 |
目的 基于腺苷酸活化蛋白激酶（AMPK）/核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)信号通路探讨司美格鲁肽（SEM）对大鼠冠状动脉微栓塞（CME）致心肌损伤的影响。方法 选择存活的32只大鼠随机分为假手术（Sham）组、CME组、CME+SEM组、CME+SEM+Compound C(CC,AMPK抑制剂)组，每组8只；将微栓塞球从左心室注入构建CME模型；从左心室注入生理盐水为Sham组；CME+SEM组在CME造模前4周，采用SEM进行皮下注射，剂量为1 mg/kg，每周1次，连续4周；在CME+SEM+CC组中，大鼠在CME造模前接受为期4周的SEM治疗，在CME造模前30 min，通过尾静脉注射给予CC(0.25 mg/kg，溶于无菌水)。各组在造模后24 h分别进行以下检测：应用心脏超声评估心功能；通过HE染色观察心肌组织的病理变化；利用Heidenhain染色测定心肌微梗死面积；采用ELISA法检测血清中心肌肌钙蛋白T(cTnT)水平；通过Western blot分析心脏组织中AMPK/NLRP3通路相关蛋白的表达情况。结果 与Sham组比较，CME组心功能显著下降，血清cTnT水平显著升高，心肌微梗死面积显著增加（P<0.05）；与CME组比较，CME+SEM组心功能得到显著改善，cTnT水平降低，心肌微梗死面积明显减少（P<0.05）。Sham组心肌组织形态结构正常，未见明显梗死灶；CME组心肌排列疏松，部分细胞核发生核碎裂，核溶解；SEM组心肌变性、水肿及炎症细胞浸润得到缓解。与Sham组比较，CME组p-AMPK/AMPK蛋白比值略有升高，NLRP3、消皮素D-N端（GSDMD-N）、凋亡相关斑点样蛋白（ASC）、半胱氨酸天冬氨酸蛋白酶-1 p20亚基（caspase-1 p20）、白细胞介素（IL）-1β、IL-18等蛋白水平均显著上调（P<0.05）；与CME组比较，CME+SEM组p-AMPK/AMPK蛋白比值进一步增加，NLRP3、GSDMD-N、ASC、caspase-1 p20、IL-1β、IL-18等蛋白水平均显著下降（P<0.05）。结论 SEM能够显著改善CME引发的心肌损伤，其作用机制可能与促进AMPK磷酸化、减少NLRP3炎症小体介导的炎症反应以及细胞焦亡密切相关。
Abstract：Objective To explore the effect of semaglutide(SEM) on myocardial injury induced by coronary microembolization(CME) in rats via the adenosine monophosphate-activated protein kinase(AMPK)/nucleotidebinding oligomerization domain-like receptor protein 3(NLRP3) signaling pathway.Methods Thirty-two rats were randomly assigned to four groups(n=8): the Sham group, the CME group, the CME + SEM group, and the CME + SEM + Compound C(CC, a specific inhibitor of AMPK) group. The CME model was established by injecting microembolic spheres into the left ventricle, while the Sham group received an equal volume of normal saline via left ventricular injection. The CME + SEM group received subcutaneous injections of SEM(1 mg/kg, once weekly) for 4 weeks before CME induction. For the CME + SEM + CC group, rats were treated with SEM for 4 weeks, followed by an intravenous injection of CC(0. 25 mg/kg dissolved in sterile normal saline) 30 minutes before CME modeling. 24 hours post-modeling, all groups underwent the following assessments: echocardiography to evaluate cardiac function, HE staining for myocardial histopathological analysis, Heidenhain staining to quantify the microinfarct area, ELISA to determine serum cardiac troponin T(cTnT) levels, and Western blot analysis to detect the expression of proteins related to the AMPK/NLRP3 pathway in cardiac tissues.Results Compared with the Sham group, the CME group showed significantly deteriorated cardiac function, elevated serum cTnT levels, and a marked increase in myocardial microinfarct area(P<0. 05). Compared with the CME group, the CME + SEM group exhibited significant improvements in cardiac function, decreased cTnT levels, and a remarkable reduction in myocardial microinfarct area(P<0. 05). Histopathological analysis revealed a normal myocardial structure in the Sham group without infarction. In contrast, the CME group showed disorganized myocardial arrangement, accompanied by nuclear fragmentation and karyolysis. In the CME + SEM group, myocardial degeneration, edema and inflammatory cell infiltration were obviously alleviated. Compared with Sham group, the protein ratioAMPK/AMPK slightly increased in the CME group, while the protein levels of NLRP3, gasdermin D-N domain(GSDMD-N), apoptosis-associated speck-like protein containing a CARD(ASC), caspase-1 p20, interleukin(IL)-1β, and IL-18 were markedly upregulated(P<0. 05). Notably, compared to the CME group, the CME + SEM group had a further elevated p-AMPK/AMPK ratio, while the protein levels of NLRP3, GSDMD-N, ASC, caspase-1 p20, IL-1β and IL-18 were markedly decreased(P<0. 05).Conclusion SEM significantly ameliorates CMEinduced myocardial injury, and its mechanism of action may be closely associated with promoting AMPK phosphorylation, inhibiting NLRP3 inflammasome-mediated inflammatory responses, and suppressing pyroptosis.
[1]Kleinbongard P, Heusch G. A fresh look at coronary microembolization[J]. Nat Rev Cardiol, 2022, 19(4):265-80. doi:10. 1038/s41569-021-00632-2.
[2]Heusch G, Skyschally A, Kleinbongard P. Coronary microembolization and microvascular dysfunction[J]. Int J Cardiol, 2018,258:17-23. doi:10. 1016/j. ijcard. 2018. 02. 010.
[3]Niu Y, Wang L, Zhang Y, et al. Pyroptosis in cardiovascular diseases:roles, mechanisms, and clinical implications[J]. Front Cardiovasc Med, 2025, 12:1629016. doi:10. 3389/fcvm.2025. 1629016.
[4]Gao Y, Shi H, Dong Z, et al. Current knowledge of pyroptosis in heart diseases[J]. J Mol Cell Cardiol, 2022, 171:81-9. doi:10. 1016/j. yjmcc. 2022. 07. 005.
[5]Liu Y, Shu J, Liu T, et al. Nicorandil protects against coronary microembolization-induced myocardial injury by suppressing cardiomyocyte pyroptosis via the AMPK/TXNIP/NLRP3 signaling pathway[J]. Eur J Pharmacol, 2022, 936:175365. doi:10. 1016/j. ejphar. 2022. 175365.
[6]Sorli C, Harashima S I, Tsoukas G M, et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes(SUSTAIN 1):a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial[J]. Lancet Diabetes Endocrinol, 2017, 5(4):251-60. doi:10. 1016/S2213-8587(17)30013-X.
[7]Lee M M Y, Sattar N, Pop-Busui R, et al. Cardiovascular and kidney outcomes and mortality with long-acting injectable and oral glucagon-like peptide 1 receptor agonists in individuals with type2 diabetes:a systematic review and meta-analysis of randomized trials[J]. Diabetes Care, 2025, 48(5):846-59. doi:10. 2337/dc25-0241.
[8]García-Vega D, Sánchez-López D, Rodríguez-Carnero G, et al.Semaglutide modulates prothrombotic and atherosclerotic mechanisms, associated with epicardial fat, neutrophils and endothelial cells network[J]. Cardiovasc Diabetol, 2024, 23(1):1. doi:10. 1186/s12933-023-02096-9.
[9]Pan X, Yang L, Wang S, et al. Semaglutide ameliorates obesityinduced cardiac inflammation and oxidative stress mediated via reduction of neutrophil Cxcl2, S100a8, and S100a9 expression[J].Mol Cell Biochem, 2024, 479(5):1133-47. doi:10. 1007/s11010-023-04784-2.
[10]靳丽丽，郄涛，李立琴.司美格鲁肽通过调控AMPK/mTOR/ULK1通路介导的自噬减轻缺氧/复氧AC16人心肌细胞炎症损伤[J].中国临床药理学与治疗学，2025, 30(8):1058-66.doi:10. 12092/j. issn. 1009-2501. 2025. 08. 006.[10]Jin L L, Qie T, Li L Q. Semaglutide alleviates hypoxia/reoxygenation-induced inflammatory injury of AC16 human cardiomyocytes by regulating autophagy through AMPK/mTOR/ULK1pathway[J]. Chin J Clin Pharmacol Ther, 2025, 30(8):1058-66. doi:10. 12092/j. issn. 1009-2501. 2025. 08. 006.
[11]Li H, Yang H, Qin Z, et al. Colchicine ameliorates myocardial injury induced by coronary microembolization through suppressing pyroptosis via the AMPK/SIRT1/NLRP3 signaling pathway[J].BMC Cardiovasc Disord, 2024, 24(1):23. doi:10. 1186/s12872-023-03697-8.
[12]Yang H F, Li H Q, Wang Q, et al. Semaglutide ameliorates coronary microembolization-induced injury by suppressing apoptosis and inflammation via the HMGB1/RAGE/NF-κB p65 pathway[J]. J Geriatr Cardiol, 2026, 23(2):83-99. doi:10. 26599/1671-5411. 2026. 02. 001.
[13]Hu C K, He L, Huang W Z, et al. Divergent splicing factor SRSF1 signaling promotes inflammation post-CME:the SRSF1/ENPP3 axis acts via inhibition of BRD4 O-GlcNAcylation to enhance NF-κB activation and accelerate heart failure[J]. Theranostics, 2025, 15(14):6839-56. doi:10. 7150/thno. 115402.
[14]Luo C J, Li T, Li H L, et al. Resveratrol pretreatment alleviates NLRP3 inflammasome-mediated cardiomyocyte pyroptosis by targeting TLR4/MyD88/NF-κB signaling cascade in coronary microembolization-induced myocardial damage[J]. Korean J Physiol Pharmacol, 2023, 27(2):143-55. doi:10. 4196/kjpp. 2023. 27. 2. 143.
[15]Drucker D J. GLP-1-based therapies for diabetes, obesity and beyond[J]. Nat Rev Drug Discov, 2025, 24(8):631-50. doi:10. 1038/s41573-025-01183-8.
[16]Verma S, Petrie M C, Borlaug B A, et al. Inflammation in obesity-related HFpEF the STEP-HFpEF program[J]. J Am Coll Cardiol, 2024, 84(17):1646-62. doi:10. 1016/j. jacc.2024. 08. 028.
[17]Lin K, Wang A, Zhai C, et al. Semaglutide protects against diabetes-associated cardiac inflammation via Sirt3-dependent RKIP pathway[J]. Br J Pharmacol, 2025, 182(7):1561-81.doi:10. 1111/bph. 17327.
[18]何浩，李成，胡赛，等.重组鼠MANF通过激活SIRT1/AMPK信号通路参与脓毒症诱导心肌损伤的保护作用[J].安徽医科大学学报，2024, 59(11):1981-8. doi:10. 19405/j.cnki. issn1000-1492. 2024. 11. 013.[18]He H, Li C, Hu S, et al. Recombinant mouse MANF participates in the protection of myocardial injury induced by sepsis by activating SIRT1/AMPK signaling pathway[J]. Acta Univ Med Anhui, 2024, 59(11):1981-8. doi:10. 19405/j. cnki. issn1000-1492. 2024. 11. 013.
[19]Haye A, Ansari M A, Rahman S O, et al. Role of AMP-activated-protein kinase on cardiometabolic abnormalities in the development of diabetic cardiomyopathy:a molecular landscape[J]. Eur J Pharmacol, 2020, 888:173376. doi:10. 1016/j. ejphar.2020. 173376.
[20]Rong D, You S, Shen H M. AMPK as a regulatory node in cell death[J]. Trends Biochem Sci, 2026, 51(6):601-19. doi:10. 1016/j. tibs. 2026. 02. 006.
[21]Ren P H, Zhang Z M, Wang P, et al. Yangxinkang tablet protects against cardiac dysfunction and remodelling after myocardial infarction in rats through inhibition of AMPK/mTOR-mediated autophagy[J]. Pharm Biol, 2020, 58(1):321-7. doi:10. 1080/13880209. 2020. 1748662.
[22]Hardie D G, Ross F A, Hawley S A. AMPK:a nutrient and energy sensor that maintains energy homeostasis[J]. Nat Rev Mol Cell Biol, 2012, 13(4):251-62. doi:10. 1038/nrm3311.
基本信息:
DOI：10.19405/j.cnki.issn1000-1492.2026.08.012
中图分类号:R54
引用信息:
[1]刘阳春,杨华锋,黄万众,等.司美格鲁肽调节AMPK/NLRP3信号通路对大鼠冠状动脉微栓塞致心肌损伤的影响[J].安徽医科大学学报,2026(08):1424-1430.DOI:10.19405/j.cnki.issn1000-1492.2026.08.012.
基金信息:
国家自然科学基金项目(编号:82300376)
2026-07-21
2026-07-21
2026-07-21