https://doi.org/10.4081/ejh.2024.3983
Atorvastatin reduces calcification in valve interstitial cells via the NF-κB signalling pathway by promoting Atg5-mediated autophagy
Submitted: 31 January 2024
Accepted: 9 March 2024
Published: 12 April 2024
Accepted: 9 March 2024
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Aortic valve calcification (AVC) is a common cardiovascular disease and a risk factor for sudden death. However, the potential mechanisms and effective therapeutic drugs need to be explored. Atorvastatin is a statin that can effectively prevent cardiovascular events by lowering cholesterol levels. However, whether atorvastatin can inhibit AVC by reducing low-density lipoprotein (LDL) and its possible mechanism of action require further exploration. In the current study, we constructed an in vitro AVC model by inducing calcification of the valve interstitial cells. We found that atorvastatin significantly inhibited osteogenic differentiation, reduced the deposition of calcium nodules in valve interstitial cells, and enhanced autophagy in calcified valve interstitial cells, manifested by increased expression levels of the autophagy proteins Atg5 and LC3B-II/I and the formation of smooth autophagic flow. Atorvastatin inhibited the NF-κB signalling pathway and the expression of inflammatory factors mediated by NF-κB in calcified valve interstitial cells. The activation of the NF-κB signalling pathway led to the reversal of atorvastatin's effect on enhancing autophagy and alleviating valve interstitial cell calcification. In conclusion, atorvastatin inhibited the NF-κB signalling pathway by upregulating autophagy, thereby alleviating valve interstitial cell calcification, which was conducive to improving AVC.
Mathieu P, Arsenault BJ. CAVD: civilization aortic valve disease. Eur Heart J 2017;38:2198-200.
DOI: https://doi.org/10.1093/eurheartj/ehx219
Pawade T, Sheth T, Guzzetti E, Dweck MR, Clavel MA. Why and how to measure aortic valve calcification in patients with aortic stenosis. JACC Cardiovasc Imaging 2019;12:1835-48.
DOI: https://doi.org/10.1016/j.jcmg.2019.01.045
Moncla LM, Briend M, Bosse Y, Mathieu P. Calcific aortic valve disease: mechanisms, prevention and treatment. Nat Rev Cardiol 2023;20:546-59.
DOI: https://doi.org/10.1038/s41569-023-00845-7
Tanase DM, Valasciuc E, Gosav EM, Floria M, Costea CF, Dima N, et al. Contribution of oxidative stress (OS) in calcific aortic valve disease (CAVD): From pathophysiology to therapeutic targets. Cells 2022;11:2663.
DOI: https://doi.org/10.3390/cells11172663
Huang Y, Jiang C, Chen L, Han J, Liu M, Zhou T, et al. Gli1 promotes the phenotypic transformation of valve interstitial cells through Hedgehog pathway activation exacerbating calcific aortic valve disease. Int J Biol Sci 2023;19:2053-66.
DOI: https://doi.org/10.7150/ijbs.74123
Kutryb-Zajac B, Jablonska P, Hebanowska A, Lango R, Rogowski J, Slominska EM, et al. Statin treatment of patients with calcific aortic valve disease modulates extracellular adenosine metabolism on the cell surface of the aortic valve. Nucleosides Nucleotides Nucleic Acids 2020;39:1389-99.
DOI: https://doi.org/10.1080/15257770.2020.1733603
Kraler S, Blaser MC, Aikawa E, Camici GG, Luscher TF. Calcific aortic valve disease: from molecular and cellular mechanisms to medical therapy. Eur Heart J 2022;43:683-97.
DOI: https://doi.org/10.1093/eurheartj/ehab757
Qiao E, Huang Z, Wang W. Exploring potential genes and pathways related to calcific aortic valve disease. Gene 2022;808:145987.
DOI: https://doi.org/10.1016/j.gene.2021.145987
Sikura KE, Combi Z, Potor L, Szerafin T, Hendrik Z, Mehes G, et al. Hydrogen sulfide inhibits aortic valve calcification in heart via regulating RUNX2 by NF-kappaB, a link between inflammation and mineralization. J Adv Res 2021;27:165-76.
DOI: https://doi.org/10.1016/j.jare.2020.07.005
Wang S, Yu H, Gao J, Chen J, He P, Zhong H, et al. PALMD regulates aortic valve calcification via altered glycolysis and NF-kappaB-mediated inflammation. J Biol Chem 2022;298:101887.
DOI: https://doi.org/10.1016/j.jbc.2022.101887
Peng X, Wang Y, Li H, Fan J, Shen J, Yu X, et al. ATG5-mediated autophagy suppresses NF-kappaB signaling to limit epithelial inflammatory response to kidney injury. Cell Death Dis 2019;10:253.
DOI: https://doi.org/10.1038/s41419-019-1483-7
Liu X, Zheng Q, Wang K, Luo J, Wang Z, Li H, et al. Sam68 promotes osteogenic differentiation of aortic valvular interstitial cells by TNF-alpha/STAT3/autophagy axis. J Cell Commun Signal 2023;17:863-79.
DOI: https://doi.org/10.1007/s12079-023-00733-2
Wei MF, Cheng CH, Wen SY, Lin JC, Chen YH, Wang CW, et al. AAtorvastatin attenuates radiotherapy-induced intestinal damage through activation of autophagy and antioxidant effects. Oxid Med Cell Longev 2022;2022:7957255.
DOI: https://doi.org/10.1155/2022/7957255
Jiang S, Chou WC, Tao L, Qiu Z, Gao G. Atorvastatin ameliorates doxorubicin-induced cardiomyopathy by regulating the autophagy-lysosome pathway and its upstream regulatory factor transcription factor EB. J Cardiovasc Pharm 2022;80:732-8.
DOI: https://doi.org/10.1097/FJC.0000000000001334
Chen J, Yan J, Li S, Zhu J, Zhou J, Li J, et al. Atorvastatin inhibited TNF-alpha induced matrix degradation in rat nucleus pulposus cells by suppressing NLRP3 inflammasome activity and inducing autophagy through NF-kappaB signaling. Cell Cycle 2021;20:2160-73.
DOI: https://doi.org/10.1080/15384101.2021.1973707
Li S, Luo Z, Su S, Wen L, Xian G, Zhao J, et al. Targeted inhibition of PTPN22 is a novel approach to alleviate osteogenic responses in aortic valve interstitial cells and aortic valve lesions in mice. BMC Med 2023;21:252.
DOI: https://doi.org/10.1186/s12916-023-02888-6
Adams SP, Tsang M, Wright JM. Lipid-lowering efficacy of atorvastatin. Cochrane Database Syst Rev 2015;2015:CD008226.
Kristiansen O, Vethe NT, Peersen K, Wang FM, Sverre E, Prunes JE, et al. Effect of atorvastatin on muscle symptoms in coronary heart disease patients with self-perceived statin muscle side effects: a randomized, double-blinded crossover trial. Eur Heart J Cardiovasc Pharmacother 2021;7:507-16.
DOI: https://doi.org/10.1093/ehjcvp/pvaa076
Huang P, Wang L, Li Q, Tian X, Xu J, Xu J, et al. Atorvastatin enhances the therapeutic efficacy of mesenchymal stem cells-derived exosomes in acute myocardial infarction via up-regulating long non-coding RNA H19. Cardiovasc Res 2020;116:353-67.
DOI: https://doi.org/10.1093/cvr/cvz139
Sun D, Zhang F, Ma T, Zhang Y, Liang Z. Atorvastatin alleviates left ventricular remodeling in isoproterenol-induced chronic heart failure in rats by regulating the RhoA/Rho kinase signaling pathway. Pharmacol Rep 2020;72:903-11.
DOI: https://doi.org/10.1007/s43440-020-00085-3
Dichtl W, Alber HF, Feuchtner GM, Hintringer F, Reinthaler M, Bartel T, et al. Prognosis and risk factors in patients with asymptomatic aortic stenosis and their modulation by atorvastatin (20 mg). Am J Cardiol 2008;102:743-8.
DOI: https://doi.org/10.1016/j.amjcard.2008.04.060
Kessler JR, Bluemn TS, DeCero SA, Dutta P, Thatcher K, Mahnke DK, et al. Exploring molecular profiles of calcification in aortic vascular smooth muscle cells and aortic valvular interstitial cells. J Mol Cell Cardiol 2023;183:1-13.
DOI: https://doi.org/10.1016/j.yjmcc.2023.08.001
Dharmarajan S, Speer MY, Pierce K, Lally J, Leaf EM, Lin ME, et al. Role of Runx2 in calcific aortic valve disease in mouse models. Front Cardiovasc Med 2021;8:687210.
DOI: https://doi.org/10.3389/fcvm.2021.687210
Jinnouchi H, Sato Y, Sakamoto A, Cornelissen A, Mori M, Kawakami R, et al. Calcium deposition within coronary atherosclerotic lesion: Implications for plaque stability. Atherosclerosis 2020;306:85-95.
DOI: https://doi.org/10.1016/j.atherosclerosis.2020.05.017
Yamazaki T, Bravo-San PJ, Galluzzi L, Kroemer G, Pietrocola F. Autophagy in the cancer-immunity dialogue. Adv Drug Deliver Rev 2021;169:40-50.
DOI: https://doi.org/10.1016/j.addr.2020.12.003
Fang J, Qian Y, Chen J, Xu D, Cao N, Zhu G, et al. Human antigen R regulates autophagic flux by stabilizing autophagy-associated mRNA in calcific aortic valve disease. Cardiovasc Res 2023;119:2117-29.
DOI: https://doi.org/10.1093/cvr/cvad077
Geng B, Chen X, Chi J, Li F, Yim WY, Wang K, et al. Platelet membrane-coated alterbrassicene A nanoparticle inhibits calcification of the aortic valve by suppressing phosphorylation P65 NF-kappaB. Theranostics 2023;13:3781-93.
DOI: https://doi.org/10.7150/thno.85323
Lindman BR, Clavel MA, Mathieu P, Iung B, Lancellotti P, Otto CM, et al. Calcific aortic stenosis. Nat Rev Dis Primers 2016;2:16006.
DOI: https://doi.org/10.1038/nrdp.2016.6
Dolcet X, Llobet D, Pallares J, Matias-Guiu X. NF-kB in development and progression of human cancer. Virchows Arch 2005;446:475-82.
DOI: https://doi.org/10.1007/s00428-005-1264-9
Li SJ, Cheng WL, Kao YH, Chung CC, Trang NN, Chen YJ. Melatonin inhibits NF-kappaB/CREB/Runx2 signaling and alleviates aortic valve calcification. Front Cardiovasc Med 2022;9:885293.
DOI: https://doi.org/10.3389/fcvm.2022.885293
How to Cite
Chen, M., & Liu, S. (2024). Atorvastatin reduces calcification in valve interstitial cells <i>via</i> the NF-κB signalling pathway by promoting Atg5-mediated autophagy. European Journal of Histochemistry, 68(2). https://doi.org/10.4081/ejh.2024.3983
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