[1]倪倩 颜开萍 李淑娟 徐敏 顾佳雨 黄晓琴 袁乙.AMPK/PGC-1α通路对尿毒症心肌病大鼠心脏损伤及线粒体能量代谢的调控机制[J].心血管病学进展,2024,(12):1138.[doi:10.16806/j.cnki.issn.1004-3934.2024.12.018]
　NI QianYAN KaipingLI ShujuanXU MinGU JiayuHUANG XiaoqinYUAN Yi.Regulation Mechanism of AMPK/PGC-1 Pathway on Cardiac Injury and Mitochondrial Energy Metabolism in Rats With Uremic Cardiomyopathy[J].Advances in Cardiovascular Diseases,2024,(12):1138.[doi:10.16806/j.cnki.issn.1004-3934.2024.12.018]
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AMPK/PGC-1α通路对尿毒症心肌病大鼠心脏损伤及线粒体能量代谢的调控机制()
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《心血管病学进展》[ISSN:51-1187/R/CN:1004-3934]

卷:
期数:
2024年12期
页码:
1138
栏目:
论著
出版日期:
2024-12-25

文章信息/Info

Title:
Regulation Mechanism of AMPK/PGC-1 Pathway on Cardiac Injury and Mitochondrial Energy Metabolism in Rats With Uremic Cardiomyopathy
作者:
倪倩 颜开萍 李淑娟 徐敏 顾佳雨 黄晓琴 袁乙
(盐城市第一人民医院/南京大学医学院附属盐城第一医院/南通大学第四附属医院/江苏医药职业学院第一附属医院肾内科 江苏 盐城 224000)
Author(s):
NI QianYAN KaipingLI ShujuanXU MinGU JiayuHUANG XiaoqinYUAN Yi
(Department of Nephrology,The First People’s Hospital of Yancheng City Affiliated to Nanjing Medical University,The Fourth Affiliated Hospital of Nantong University,The First Affiliated Hospital of Jiangsu Vocational College of Medicine ,Yancheng 224000,Jiangsu,China)
关键词:
尿毒症心肌病; AMPK/PGC-1α通路; 线粒体能量代谢
Keywords:
Uremic cardiomyopathy;  AMPK/PGC-1 pathway;  Mitochondrial energy metabolism
DOI:
10.16806/j.cnki.issn.1004-3934.2024.12.018
摘要:
目的 探究AMP激活蛋白激酶（AMPK）/过氧化物酶体增殖物激活受体γ辅助因子1-α（PGC-1α）通路在尿毒症心肌病（UCM）大鼠的心脏损伤及线粒体能量代谢中的调控机制。方法 将30只大鼠随机分为3组：对照组、UCM组、盐酸阿霉素（DOX）组，每组10只。超声心动图检测心功能指标：左室射血分数（LVEF）、左心室舒张末期内径（LVIDD）、E/A，HE染色检测心肌组织病理变化，Masson染色检测心肌组织纤维化水平，Western blotting检测心肌组织AMPK、PGC-1α、磷酸化AMPK（p-AMPK）、p-PGC-1α蛋白水平，JC-1试剂盒检测线粒体膜电位，线粒体呼吸链复合物Ⅰ~Ⅴ试剂盒检测线粒体复合物Ⅰ~Ⅴ活性，ATP含量检测试剂盒检测ATP水平，透射电镜检测心肌线粒体超微结构。 结果 与对照组相比，UCM组大鼠心肌纤维紊乱、断裂，心肌间隙可见胶原大量沉积，大鼠EF无显著性差异，LVIDD增加，E/A降低（P<0.05），心肌组织中AMPK、PGC-1α表达无显著性差异，p-AMPK、p-PGC-1α蛋白表达增加（P<0.05），心肌线粒体肿胀、空泡化，且部分线粒体嵴消失，线粒体膜电位减少，ATP含量减少（P<0.05）心肌线粒体呼吸链复合物Ⅰ~Ⅴ活性均减少（P<0.05）；与UCM组相比，DOX组大鼠心肌纤维损伤改善，心肌间隙胶原沉积减少，EF无显著性差异，LVIDD减少，E/A增加（P<0.05），心肌组织中AMPK、PGC-1α表达无显著性差异，p-AMPK、p-PGC-1α蛋白表达减少（P<0.05），心肌线粒体结构改善，线粒体膜电位增加，ATP含量增加（P<0.05），心肌线粒体呼吸链复合物Ⅰ~Ⅴ活性均增加（P<0.05）。结论 抑制AMPK/PGC-1α通路磷酸化可改善UCM大鼠心功能及心肌组织病理学变化，改善线粒体探讨线粒体能量代谢。
Abstract:
Objective To investigate the regulatory mechanism of AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma cofactor-1α (PGC-1α) pathway on heart injury and mitochondrial energy metabolism in rats with uremic cardiomyopathy (UCM). Methods Thirty rats were randomly divided into three groups: control group,UCM group and doxorubicin (DOX) group,with 10 rats in each group. Left ventricular ejection fraction (LVEF),left ventricular end-diastolic diameter (LVIDD) and E/A were measured by echocardiography. H&E staining was used to detect the pathological changes of myocardial tissue. Masson staining was used to detect myocardial fibrosis. Western blotting was used to detect the protein levels of AMPK,PGC-1α,phosphorylated AMPK (p-AMPK) and p-PGC-1α in myocardial tissue. Mitochondrial membrane potential was measured by JC-1 kit. The activity of mitochondrial respiratory chain complex Ⅰ~Ⅴ was detected by mitochondrial respiratory chain complex Ⅰ~Ⅴ kit. ATP level was detected by ATP content detection kit. The ultrastructure of myocardial mitochondria was detected by transmission electron microscope. Results Compared with the control group ,the myocardium fibers in UCM group were disorganized and broken,and A large amount of collagen could be seen in the myocardium space. There was no significant difference in EF,LVIDD thickness increased,E/A decreased (P<0.05),there was no significant difference in the expression of AMPK and PGC-1α in myocardial tissue,while the expression of p-AMPK and p-PGC-1α increased (P<0.05),myocardial mitochondria were swollen and vacuolated,some mitochondrial cristae disappeared,mitochondrial membrane potential decreased,and ATP content decreased (P<0.05) The activities of myocardial mitochondrial respiratory chain complex Ⅰ~Ⅴ were decreased ( P<0.05); Compared with UCM group,myocardial fiber injury was improved,collagen deposition in myocardial space was reduced,EF was not significantly different,LVIDD thickness was decreased,E/A was increased (P<0.05),there was no significant difference in the expression of AMPK and PGC-1α in myocardial tissue,and the expression of p-AMPK and p-PGC-1α decreased (P<0.05),myocardial mitochondrial structure improved,mitochondrial membrane potential increased,ATP content increased (P<0.05),the activities of myocardial mitochondrial respiratory chain complex Ⅰ~Ⅴ were increased ( P<0.05). Conclusion Inhibition of AMPK/PGC-1α pathway phosphorylation can improve cardiac function and myocardial histopathological changes in UCM rats ,improve mitochondria and explore mitochondrial energy metabolism

参考文献/References:

[1].Amador-Martínez I,García-Ballhaus J,Buelna-Chontal M,et al. Early inflammatory changes and CC chemokine ligand-8 upregulation in the heart contribute to uremic cardiomyopathy[J]. FASEB J,2021,35(8):e21761.
[2].D’Agostino M,Mauro D,Zicarelli M,et al. miRNAs in uremic cardiomyopathy:a comprehensive review[J]. Int J Mol Sci,2023,24(6):5425.
[3].Wu S,Zou MH. AMPK,Mitochondrial function,and cardiovascular disease[J]. Int J Mol Sci,2020,21(14):4987.
[4].Halling JF,Pilegaard H. PGC-1α-mediated regulation of mitochondrial function and physiological implications[J]. Appl Physiol Nutr Metab,2020,45(9):927-936.
[5].Wang D,Cao L,Zhou X,et al. Mitigation of honokiol on fluoride-induced mitochondrial oxidative stress,mitochondrial dysfunction,and cognitive deficits through activating AMPK/PGC-1α/Sirt3[J]. J Hazard Mater,2022,437:129381.
[6].Sun J,Song FH,Wu JY,et al. Sestrin2 overexpression attenuates osteoarthritis pain via induction of AMPK/PGC-1α-mediated mitochondrial biogenesis and suppression of neuroinflammation[J]. Brain Behav Immun,2022,102:53-70.
[7].Tong D,Xu E,Ge R,et al. Aspirin alleviates cisplatin-induced acute kidney injury through the AMPK-PGC-1α signaling pathway[J]. Chem Biol Interact,2023,380:110536.
[8].Chen Q,Li Z,Liu B,et al. [Protective effects of Zhenwutang on cardiac function in mice with uremic cardiomyopathy induced by subtotal nephrectomy][J]. Nan Fang Yi Ke Da Xue Xue Bao,2015,35(12):1725-1728.
[9].Thome T,Kim K,Dong G,et al. The role of mitochondrial and redox alterations in the skeletal myopathy associated with chronic kidney disease[J]. Antioxid Redox Signal,2023,38(4-6):318-337.
[10].Thome T,Kumar RA,Burke SK,et al. Impaired muscle mitochondrial energetics is associated with uremic metabolite accumulation in chronic kidney disease[J]. JCI Insight,2020,6(1):e139826.
[11].保靖夫. 啮齿类动物尿毒症心肌病模型构建研究[D]. 南方医科大学,2022.
[12].Sárk?zy M,Watzinger S,Kovács ZZA,et al. Neuregulin-1β improves uremic cardiomyopathy and renal dysfunction in rats[J]. JACC Basic Transl Sci,2023,8(9):1160-1176.
[13].Sárk?zy M,Kovács ZZA,Kovács MG,et al. Mechanisms and modulation of oxidative/nitrative stress in type 4 cardio-renal syndrome and renal sarcopenia[J]. Front Physiol,2018,9:1648.
[14]. Steinberg GR ,Hardie DG. New insights into activation and function of the AMPK[J]. Nat Rev Mol Cell Biol,2023,24(4):255-272.
[15].Entezari M,Hashemi D,Taheriazam A,et al. AMPK signaling in diabetes mellitus,insulin resistance and diabetic complications:a pre-clinical and clinical investigation. Biomed Pharmacother,2022,146:112563.
[16].Yang K,Xu X,Nie L,et al. Indoxyl sulfate induces oxidative stress and hypertrophy in cardiomyocytes by inhibiting the AMPK/UCP2 signaling pathway[J]. Toxicol Lett,2015,234(2):110-119.
[17].Rius-Pérez S,Torres-Cuevas I,Millán I,et al. PGC-1α,inflammation,and oxidative stress:an integrative view in metabolism[J]. Oxid Med Cell Longev,2020,2020:1452696.
[18].Esteras N,Abramov AY. Nrf2 as a regulator of mitochondrial function:Energy metabolism and beyond[J]. Free Radic Biol Med,2022,189:136-153.
[19].[19]Yang L,Chen Y,Zhou J,et al. Aconitine induces mitochondrial energy metabolism dysfunction through inhibition of AMPK signaling and interference with mitochondrial dynamics in SH-SY5Y cells[J]. Toxicol Lett,2021,347:36-44.

更新日期/Last Update: 2025-01-08