Research progress of myocardial fibrosis and AMPK-mTOR-ULK1 signaling pathway

doi:10.3760/cma.j.issn.1007-1245.2024.08.014

Abstract

Abstract:

Myocardial fibrosis is an important pathological change in the occurrence and development of many cardiovascular diseases, and it is also the pathological basis of heart pump failure and adverse cardiovascular events, which is mainly manifested by excessive deposition of extracellular matrix (ECM) and continuous proliferation of cardiac fibroblasts (CFs). Adenylate activated protein kinase (AMPK) signaling pathway is the main system to mediate phosphorylation. AMPK activates autophagy, inhibits mammalian target of rapamycin (mTOR), and phosphorylates Unc-51-like autophagy activated kinase 1(ULK1). AMPK signaling pathway plays an important role in the occurrence and development of myocardial fibrosis. This paper analyzes the role of AMPK-mTOR-ULK1 signaling pathway in myocardial fibrosis, hoping to provide guidance for the treatment of myocardial fibrosis.

Key words:

Myocardial fibrosis, AMPK-mTOR-ULK1, Signaling pathway, Review

摘要：

心肌纤维化是诸多心血管疾患发生发展的重要病理变化，也是造成心脏泵衰竭及不良心血管事件的病理基础，其主要表现为细胞外基质（ECM）的过度沉积与成纤维细胞（CFs）的不断增殖。腺苷酸活化蛋白激酶（AMPK）信号通路是介导磷酸化的主要系统，AMPK激活自噬，可抑制雷帕霉素靶蛋白（mTOR），也可磷酸化Unc-51样自噬激活激酶1（ULK1）；AMPK信号通路在心肌纤维化的发生发展过程中起到了重要作用，本文通过分析AMPK-mTOR-ULK1信号通路在心肌纤维化中的作用，以期为心肌纤维化的治疗提供指导。

关键词:

心肌纤维化, AMPK-mTOR-ULK1, 信号通路, 综述

Liu Zhiqiang, Zhang Cui, Dong Wenjing, Liu Zhen, Sun Jingwu.

Research progress of myocardial fibrosis and AMPK-mTOR-ULK1 signaling pathway [J]. International Medicine and Health Guidance News, 2024, 30(8): 1297-1300.

刘志强张翠董文敬刘振孙经武.

心肌纤维化与AMPK-mTOR-ULK1信号通路研究进展 [J]. 国际医药卫生导报, 2024, 30(8): 1297-1300.

References

[1] Frangogiannis NG. Cardiac fibrosis[J]. Cardiovasc Res, 2021, 117(6):1450-1488. DOI: 10.1093/cvr/cvaa324.
[2] Frangogiannis NG. Cardiac fibrosis: cell biological mechanisms, molecular pathways and therapeutic opportunities[J]. Mol Aspects Med, 2019, 65:70-99. DOI: 10.1016/j.mam.2018.07.001.
[3] Theocharis AD, Skandalis SS, Gialeli C, et al. Extracellular matrix structure[J]. Adv Drug Deliv Rev, 2016, 97:4-27. DOI: 10.1016/j.addr.2015.11.001.
[4] Hinderer S, Schenke-Layland K. Cardiac fibrosis - a short review of causes and therapeutic strategies[J]. Adv Drug Deliv Rev, 2019, 146:77-82. DOI: 10.1016/j.addr.2019. 05.011.
[5] Gao L, Wang LY, Liu ZQ, et al. TNAP inhibition attenuates cardiac fibrosis induced by myocardial infarction through deactivating TGF-β1/Smads and activating P53 signaling pathways[J]. Cell Death Dis, 2020, 11(1):44. DOI: 10.1038/s41419-020-2243-4.
[6] de Boer RA, De Keulenaer G, Bauersachs J, et al. Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology[J]. Eur J Heart Fail, 2019, 21(3):272-285. DOI: 10.1002/ejhf.1406.
[7] Frangogiannis NG. The extracellular matrix in ischemic and nonischemic heart failure[J]. Circ Res, 2019, 125(1):117-146. DOI: 10.1161/CIRCRESAHA.119.311148.
[8] Eijgenraam TR, Silljé HHW, de Boer RA. Current understanding of fibrosis in genetic cardiomyopathies[J]. Trends Cardiovasc Med, 2020, 30(6):353-361. DOI: 10.1016/j.tcm.2019.09.003.
[9] Xiao H, Li H, Wang JJ, et al. IL-18 cleavage triggers cardiac inflammation and fibrosis upon β-adrenergic insult[J]. Eur Heart J, 2018, 39(1):60-69. DOI: 10.1093/eurheartj/ehx261.
[10] Tsutsui H, Kinugawa S, Matsushima S. Oxidative stress and heart failure[J]. Am J Physiol Heart Circ Physiol, 2011, 301(6):H2181-H2190. DOI: 10.1152/ajpheart.00554. 2011.
[11] Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling[J]. Cell Signal, 2012, 24(5):981-990. DOI: 10.1016/j.cellsig.2012.01.008.
[12] Wang X, Zhang G, Dasgupta S, et al. ATF4 protects the heart from failure by antagonizing oxidative stress[J]. Circ Res, 2022, 131(1):91-105. DOI: 10.1161/CIRCRESAHA. 122.321050.
[13] Lin P, Tong X, Xue F, et al. Polystyrene nanoplastics exacerbate lipopolysaccharide-induced myocardial fibrosis and autophagy in mice via ROS/TGF-β1/Smad[J]. Toxicology, 2022, 480:153338. DOI: 10.1016/j.tox.2022. 153338.
[14] Tian Y, Luo J, Xu Q, et al. Macrophage depletion protects against endothelial dysfunction and cardiac remodeling in angiotensin II hypertensive mice[J]. Clin Exp Hypertens, 2021, 43(8):699-706. DOI: 10.1080/10641963.2021.1945075.
[15] Abareshi A, Norouzi F, Asgharzadeh F, et al. Effect of angiotensin-converting enzyme inhibitor on cardiac fibrosis and oxidative stress status in lipopolysaccharide-induced inflammation model in rats[J]. Int J Prev Med, 2017, 8:69. DOI: 10.4103/ijpvm.IJPVM_322_16.
[16] Carling D. AMPK signalling in health and disease[J]. Curr Opin Cell Biol, 2017, 45:31-37. DOI: 10.1016/j.ceb.2017.01.005.
[17] Ge Y, Zhou M, Chen C, et al. Role of AMPK mediated pathways in autophagy and aging[J]. Biochimie, 2022, 195:100-113. DOI: 10.1016/j.biochi.2021.11.008.
[18] Saha S, Panigrahi DP, Patil S, et al. Autophagy in health and disease: a comprehensive review[J]. Biomed Pharmacother, 2018, 104:485-495. DOI: 10.1016/j.biopha.2018.05.007.
[19] Wu X, Liu Z, Yu XY, et al. Autophagy and cardiac diseases: therapeutic potential of natural products[J]. Med Res Rev, 2021, 41(1):314-341. DOI: 10.1002/med.21733.
[20] Vanhoutte D, Schips TG, Vo A, et al. Thbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy[J]. Nat Commun, 2021, 12(1):3928. DOI: 10.1038/s41467-021-24215-4.
[21] Tong M, Saito T, Zhai P, et al. Alternative mitophagy protects the heart against obesity-associated cardiomyopathy[J]. Circ Res, 2021, 129(12):1105-1121. DOI: 10.1161/CIRCRESAHA.121.319377.
[22] Wu S, Zou MH. AMPK, mitochondrial function, and cardiovascular disease[J]. Int J Mol Sci, 2020, 21(14):4987. DOI: 10.3390/ijms21144987.
[23] Wouters BG, van den Beucken T, Magagnin MG, et al. Control of the hypoxic response through regulation of mRNA translation[J]. Semin Cell Dev Biol, 2005, 16(4-5):487-501. DOI: 10.1016/j.semcdb.2005.03.009.
[24] Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint[J]. Mol Cell, 2008, 30(2):214-226. DOI: 10.1016/j.molcel.2008.03.003.
[25] Chan EY. mTORC1 phosphorylates the ULK1-mAtg13-FIP200 autophagy regulatory complex[J]. Sci Signal, 2009, 2(84):pe51. DOI: 10.1126/scisignal.284pe51.
[26] Egan DF, Shackelford DB, Mihaylova MM, et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy[J]. Science, 2011, 331(6016):456-461. DOI: 10.1126/science.1196371.
[27] Han M, Zhou B. Role of cardiac fibroblasts in cardiac injury and repair[J]. Curr Cardiol Rep, 2022, 24(3):295-304. DOI: 10.1007/s11886-022-01647-y.
[28] Yang M, Song JJ, Yang XC, et al. MiRNA-122-5p inhibitor abolishes angiotensin II-mediated loss of autophagy and promotion of apoptosis in rat cardiofibroblasts by modulation of the apelin-AMPK-mTOR signaling[J]. In Vitro Cell Dev Biol Anim, 2022, 58(2):136-148. DOI: 10.1007/s11626-022-00651-4.
[29] Auciello FR, Ross FA, Ikematsu N, et al. Oxidative stress activates AMPK in cultured cells primarily by increasing cellular AMP and/or ADP[J]. FEBS Lett, 2014, 588(18):3361-3366. DOI: 10.1016/j.febslet.2014.07.025.
[30] Kurose H, Mangmool S. Myofibroblasts and inflammatory cells as players of cardiac fibrosis[J]. Arch Pharm Res, 2016, 39(8):1100-1113. DOI: 10.1007/s12272-016- 0809-6.
[31] Kurose H. Cardiac fibrosis and fibroblasts[J]. Cells, 2021, 10(7):1716. DOI: 10.3390/cells10071716.
[32] Ishikane S, Arioka M, Takahashi-Yanaga F. Promising small molecule anti-fibrotic agents: newly developed or repositioned drugs targeting myofibroblast transdifferentiation[J]. Biochem Pharmacol, 2023, 214:115663. DOI: 10.1016/j.bcp.2023.115663.
[33] Mishra R, Cool BL, Laderoute KR, et al. AMP-activated protein kinase inhibits transforming growth factor-beta-induced Smad3-dependent transcription and myofibroblast transdifferentiation[J]. J Biol Chem, 2008, 283(16):10461-10469. DOI: 10.1074/jbc.M800902200.
[34] Xiao Y, Ye J, Zhou Y, et al. Baicalin inhibits pressure overload-induced cardiac fibrosis through regulating AMPK/TGF-β/Smads signaling pathway[J]. Arch Biochem Biophys, 2018, 640:37-46. DOI: 10.1016/j.abb.2018. 01.006.
[35] Kong D, Zhang Z, Chen L, et al. Curcumin blunts epithelial-mesenchymal transition of hepatocytes to alleviate hepatic fibrosis through regulating oxidative stress and autophagy[J]. Redox Biol, 2020, 36:101600. DOI: 10.1016/j.redox.2020.101600.
[36] Jin D, Zhao Y, Sun Y, et al. Jiedu Tongluo Baoshen formula enhances renal tubular epithelial cell autophagy to prevent renal fibrosis by activating SIRT1/LKB1/AMPK pathway[J]. Biomed Pharmacother, 2023, 160:114340. DOI: 10.1016/j.biopha.2023.114340.
[37] Huang H, Wang T, Wang L, et al. Saponins of Panax japonicus ameliorates cardiac aging phenotype in aging rats by enhancing basal autophagy through AMPK/mTOR/ULK1 pathway[J]. Exp Gerontol, 2023, 182:112305. DOI: 10.1016/j.exger.2023.112305.
[38] Wang L, Yuan D, Zheng J, et al. Chikusetsu saponin IVa attenuates isoprenaline-induced myocardial fibrosis in mice through activation autophagy mediated by AMPK/mTOR/ULK1 signaling[J]. Phytomedicine, 2019, 58:152764. DOI: 10.1016/j.phymed.2018.11.024.
[39] Huang L, Chen J, Wu D, et al. Berberine attenuates IL-1β-induced damage of nucleus pulposus cells via activating the AMPK/mTOR/Ulk1 pathway[J]. Biomed Res Int, 2022, 2022:6133629. DOI: 10.1155/2022/6133629.
[40] Wong SK, Chin KY, Ima-Nirwana S. Berberine and musculoskeletal disorders: the therapeutic potential and underlying molecular mechanisms[J]. Phytomedicine, 2020, 73:152892. DOI: 10.1016/j.phymed.2019.152892.
[41] Ranek MJ, Kokkonen-Simon KM, Chen A, et al. PKG1-modified TSC2 regulates mTORC1 activity to counter adverse cardiac stress[J]. Nature, 2019, 566(7743):264-269. DOI: 10.1038/s41586-019-0895-y.
[42] Wang K, Li Z, Ding Y, et al. Klotho improves cardiac fibrosis, inflammatory cytokines, ferroptosis, and oxidative stress in mice with myocardial infarction[J]. J Physiol Biochem, 2023, 79(2):341-353. DOI: 10.1007/s13105-023-00945-5.
[43] Zhao Y, Sun D, Chen Y, et al. Si-Miao-Yong-An Decoction attenuates isoprenaline-induced myocardial fibrosis in AMPK-driven Akt/mTOR and TGF-β/SMAD3 pathways[J]. Biomed Pharmacother, 2020, 130:110522. DOI: 10.1016/j.biopha.2020.110522.
[44] Chen WR, Yang JQ, Liu F, et al. Melatonin attenuates vascular calcification by activating autophagy via an AMPK/mTOR/ULK1 signaling pathway[J]. Exp Cell Res, 2020, 389(1):111883. DOI: 10.1016/j.yexcr.2020.111883.