The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Lactate promotes vascular smooth muscle cell switch to a synthetic phenotype by inhibiting miR-23b expression

  • Hu, Yanchao (Department of Cardiovascular Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University) ;
  • Zhang, Chunyan (Department of Cardiovascular Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University) ;
  • Fan, Yajie (Department of Cardiovascular Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University) ;
  • Zhang, Yan (Department of Cardiovascular Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University) ;
  • Wang, Yiwen (Department of Cardiovascular Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University) ;
  • Wang, Congxia (Department of Cardiovascular Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University)
  • Received : 2022.07.18
  • Accepted : 2022.09.13
  • Published : 2022.11.01
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Abstract

Recent research indicates that lactate promotes the switching of vascular smooth muscle cells (VSMCs) to a synthetic phenotype, which has been implicated in various vascular diseases. This study aimed to investigate the effects of lactate on the VSMC phenotype switch and the underlying mechanism. The CCK-8 method was used to assess cell viability. The microRNAs and mRNAs levels were evaluated using quantitative PCR. Targets of microRNA were predicted using online tools and confirmed using a luciferase reporter assay. We found that lactate promoted the switch of VSMCs to a synthetic phenotype, as evidenced by an increase in VSMC proliferation, mitochondrial activity, migration, and synthesis but a decrease in VSMC apoptosis. Lactate inhibited miR-23b expression in VSMCs, and miR-23b inhibited VSMC's switch to the synthetic phenotype. Lactate modulated the VSMC phenotype through downregulation of miR-23b expression, suggesting that overexpression of miR-23b using a miR-23b mimic attenuated the effects of lactate on VSMC phenotype modulation. Moreover, we discovered that SMAD family member 3 (SMAD3) was the target of miR-23b in regulating VSMC phenotype. Further findings suggested that lactate promotes VSMC switch to synthetic phenotype by targeting SMAD3 and downregulating miR-23b. These findings suggest that correcting the dysregulation of miR-23b/SMAD3 or lactate metabolism is a potential treatment for vascular diseases.

Keywords

Acknowledgement

We are very grateful for the equipment and technical support provided by The Second Affiliated Hospital of Xi'an Jiaotong University.

References

  1. Basatemur GL, Jorgensen HF, Clarke MCH, Bennett MR, Mallat Z. Vascular smooth muscle cells in atherosclerosis. Nat Rev Cardiol. 2019;16:727-744. https://doi.org/10.1038/s41569-019-0227-9
  2. Bennett MR, Sinha S, Owens GK. Vascular smooth muscle cells in atherosclerosis. Circ Res. 2016;118:692-702. https://doi.org/10.1161/CIRCRESAHA.115.306361
  3. Morrow D, Guha S, Sweeney C, Birney Y, Walshe T, O'Brien C, Walls D, Redmond EM, Cahill PA. Notch and vascular smooth muscle cell phenotype. Circ Res. 2008;103:1370-1382. https://doi.org/10.1161/CIRCRESAHA.108.187534
  4. Lacolley P, Regnault V, Avolio AP. Smooth muscle cell and arterial aging: basic and clinical aspects. Cardiovasc Res. 2018;114:513-528. https://doi.org/10.1093/cvr/cvy009
  5. Grootaert MOJ, Moulis M, Roth L, Martinet W, Vindis C, Bennett MR, De Meyer GRY. Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis. Cardiovasc Res. 2018;114:622-634. https://doi.org/10.1093/cvr/cvy007
  6. Chistiakov DA, Orekhov AN, Bobryshev YV. Vascular smooth muscle cell in atherosclerosis. Acta Physiol (Oxf). 2015;214:33-50. https://doi.org/10.1111/apha.12466
  7. Salabei JK, Hill BG. Autophagic regulation of smooth muscle cell biology. Redox Biol. 2015;4:97-103. https://doi.org/10.1016/j.redox.2014.12.007
  8. Hashimoto T, Hussien R, Oommen S, Gohil K, Brooks GA. Lactate sensitive transcription factor network in L6 cells: activation of MCT1 and mitochondrial biogenesis. FASEB J. 2007;21:2602-2612. https://doi.org/10.1096/fj.07-8174com
  9. Hirschhaeuser F, Sattler UG, Mueller-Klieser W. Lactate: a metabolic key player in cancer. Cancer Res. 2011;71:6921-6925. https://doi.org/10.1158/0008-5472.CAN-11-1457
  10. Dhup S, Dadhich RK, Porporato PE, Sonveaux P. Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis. Curr Pharm Des. 2012;18:1319-1330. https://doi.org/10.2174/138161212799504902
  11. Muller P, Duderstadt Y, Lessmann V, Muller NG. Lactate and BDNF: key mediators of exercise induced neuroplasticity? J Clin Med. 2020;9:1136. https://doi.org/10.3390/jcm9041136
  12. Baltazar F, Afonso J, Costa M, Granja S. Lactate beyond a waste metabolite: metabolic affairs and signaling in malignancy. Front Oncol 2020;10:231. https://doi.org/10.3389/fonc.2020.00231
  13. Pereira-Nunes A, Afonso J, Granja S, Baltazar F. Lactate and lactate transporters as key players in the maintenance of the Warburg effect. Adv Exp Med Biol. 2020;1219:51-74. https://doi.org/10.1007/978-3-030-34025-4_3
  14. Yang L, Gao L, Nickel T, Yang J, Zhou J, Gilbertsen A, Geng Z, Johnson C, Young B, Henke C, Gourley GR, Zhang J. Lactate promotes synthetic phenotype in vascular smooth muscle cells. Circ Res. 2017;121:1251-1262. https://doi.org/10.1161/CIRCRESAHA.117.311819
  15. Gomez-Cabrera MC, Domenech E, Vina J. Moderate exercise is an antioxidant: upregulation of antioxidant genes by training. Free Radic Biol Med. 2008;44:126-131. https://doi.org/10.1016/j.freeradbiomed.2007.02.001
  16. Griffiths-Jones S. The microRNA Registry. Nucleic Acids Res. 2004;32:D109-D111. https://doi.org/10.1093/nar/gkh023
  17. Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ. miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res. 2006;34:D140- D144. https://doi.org/10.1093/nar/gkj112
  18. Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, Hayward DC, Ball EE, Degnan B, Muller P, Spring J, Srinivasan A, Fishman M, Finnerty J, Corbo J, Levine M, Leahy P, Davidson E, Ruvkun G. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 2000;408:86-89. https://doi.org/10.1038/35040556
  19. Yang F, Chen Q, He S, Yang M, Maguire EM, An W, Afzal TA, Luong LA, Zhang L, Xiao Q. miR-22 is a novel mediator of vascular smooth muscle cell phenotypic modulation and neointima formation. Circulation. 2018;137:1824-1841. https://doi.org/10.1161/CIRCULATIONAHA.117.027799
  20. Tang Y, Yu S, Liu Y, Zhang J, Han L, Xu Z. MicroRNA-124 controls human vascular smooth muscle cell phenotypic switch via Sp1. Am J Physiol Heart Circ Physiol. 2017;313:H641-H649. https://doi.org/10.1152/ajpheart.00660.2016
  21. Iaconetti C, De Rosa S, Polimeni A, Sorrentino S, Gareri C, Carino A, Sabatino J, Colangelo M, Curcio A, Indolfi C. Down-regulation of miR-23b induces phenotypic switching of vascular smooth muscle cells in vitro and in vivo. Cardiovasc Res. 2015;107:522-533. https://doi.org/10.1093/cvr/cvv141
  22. Yue Y, Zhang Z, Zhang L, Chen S, Guo Y, Hong Y. miR-143 and miR-145 promote hypoxia-induced proliferation and migration of pulmonary arterial smooth muscle cells through regulating ABCA1 expression. Cardiovasc Pathol. 2018;37:15-25. https://doi.org/10.1016/j.carpath.2018.08.003
  23. Grundmann S, Hans FP, Kinniry S, Heinke J, Helbing T, Bluhm F, Sluijter JP, Hoefer I, Pasterkamp G, Bode C, Moser M. MicroRNA-100 regulates neovascularization by suppression of mammalian target of rapamycin in endothelial and vascular smooth muscle cells. Circulation. 2011;123:999-1009. https://doi.org/10.1161/CIRCULATIONAHA.110.000323
  24. Torella D, Iaconetti C, Catalucci D, Ellison GM, Leone A, Waring CD, Bochicchio A, Vicinanza C, Aquila I, Curcio A, Condorelli G, Indolfi C. MicroRNA-133 controls vascular smooth muscle cell phenotypic switch in vitro and vascular remodeling in vivo. Circ Res. 2011;109:880-893. https://doi.org/10.1161/CIRCRESAHA.111.240150
  25. Luo Y, Xiong W, Dong S, Liu F, Liu H, Li J. MicroRNA-146a promotes the proliferation of rat vascular smooth muscle cells by downregulating p53 signaling. Mol Med Rep. 2017;16:6940-6945. https://doi.org/10.3892/mmr.2017.7477
  26. Liu X, Cheng Y, Zhang S, Lin Y, Yang J, Zhang C. A necessary role of miR-221 and miR-222 in vascular smooth muscle cell proliferation and neointimal hyperplasia. Circ Res. 2009;104:476-487. https://doi.org/10.1161/CIRCRESAHA.108.185363
  27. Merlet E, Atassi F, Motiani RK, Mougenot N, Jacquet A, Nadaud S, Capiod T, Trebak M, Lompre AM, Marchand A. miR-424/322 regulates vascular smooth muscle cell phenotype and neointimal formation in the rat. Cardiovasc Res. 2013;98:458-468. https://doi.org/10.1093/cvr/cvt045
  28. Tang R, Mei X, Wang YC, Cui XB, Zhang G, Li W, Chen SY. LncRNA GAS5 regulates vascular smooth muscle cell cycle arrest and apoptosis via p53 pathway. Biochim Biophys Acta Mol Basis Dis. 2019;1865:2516-2525. https://doi.org/10.1016/j.bbadis.2019.05.022
  29. Haas R, Smith J, Rocher-Ros V, Nadkarni S, Montero-Melendez T, D'Acquisto F, Bland EJ, Bombardieri M, Pitzalis C, Perretti M, Marelli-Berg FM, Mauro C. Lactate regulates metabolic and proinflammatory circuits in control of T cell migration and effector functions. PLoS Biol. 2015;13:e1002202. https://doi.org/10.1371/journal.pbio.1002202
  30. Butler TM, Siegman MJ. High-energy phosphate metabolism in vascular smooth muscle. Annu Rev Physiol. 1985;47:629-643. https://doi.org/10.1146/annurev.ph.47.030185.003213
  31. Paul RJ. Functional compartmentalization of oxidative and glycolytic metabolism in vascular smooth muscle. Am J Physiol. 1983;244:C399-409. https://doi.org/10.1152/ajpcell.1983.244.5.C399
  32. Andersen LW, Mackenhauer J, Roberts JC, Berg KM, Cocchi MN, Donnino MW. Etiology and therapeutic approach to elevated lactate levels. Mayo Clin Proc. 2013;88:1127-1140. https://doi.org/10.1016/j.mayocp.2013.06.012
  33. Leite TC, Coelho RG, Da Silva D, Coelho WS, Marinho-Carvalho MM, Sola-Penna M. Lactate downregulates the glycolytic enzymes hexokinase and phosphofructokinase in diverse tissues from mice. FEBS Lett. 2011;585:92-98. https://doi.org/10.1016/j.febslet.2010.11.009
  34. Zhao LL, Wu H, Sun JL, Liao L, Cui C, Liu Q, Luo J, Tang XH, Luo W, Ma JD, Ye X, Li SJ, Yang S. MicroRNA-124 regulates lactate transportation in the muscle of largemouth bass (micropterus salmoides) under hypoxia by targeting MCT1. Aquat Toxicol. 2020;218:105359. https://doi.org/10.1016/j.aquatox.2019.105359
  35. Ping W, Senyan H, Li G, Yan C, Long L. Increased lactate in gastric cancer tumor-infiltrating lymphocytes is related to impaired T cell function due to miR-34a deregulated lactate dehydrogenase A. Cell Physiol Biochem. 2018;49:828-836. https://doi.org/10.1159/000493110
  36. Bang C, Fiedler J, Thum T. Cardiovascular importance of the microRNA-23/27/24 family. Microcirculation. 2012;19:208-214. https://doi.org/10.1111/j.1549-8719.2011.00153.x
  37. Majid S, Dar AA, Saini S, Arora S, Shahryari V, Zaman MS, Chang I, Yamamura S, Tanaka Y, Deng G, Dahiya R. miR-23b represses proto-oncogene Src kinase and functions as methylation-silenced tumor suppressor with diagnostic and prognostic significance in prostate cancer. Cancer Res. 2012;72:6435-6446. https://doi.org/10.1158/0008-5472.CAN-12-2181
  38. Zhu S, Pan W, Song X, Liu Y, Shao X, Tang Y, Liang D, He D, Wang H, Liu W, Shi Y, Harley JB, Shen N, Qian Y. The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-α. Nat Med. 2012;18:1077-1086. https://doi.org/10.1038/nm.2815
  39. Plekhanova OS, Parfyonova YV, Bibilashvily RSh, Stepanova VV, Erne P, Bobik A, Tkachuk VA. Urokinase plasminogen activator enhances neointima growth and reduces lumen size in injured carotid arteries. J Hypertens. 2000;18:1065-1069. https://doi.org/10.1097/00004872-200018080-00011
  40. Clowes AW, Clowes MM, Au YP, Reidy MA, Belin D. Smooth muscle cells express urokinase during mitogenesis and tissue-type plasminogen activator during migration in injured rat carotid artery. Circ Res. 1990;67:61-67. https://doi.org/10.1161/01.RES.67.1.61
  41. Kundi R, Hollenbeck ST, Yamanouchi D, Herman BC, Edlin R, Ryer EJ, Wang C, Tsai S, Liu B, Kent KC. Arterial gene transfer of the TGF-beta signalling protein Smad3 induces adaptive remodelling following angioplasty: a role for CTGF. Cardiovasc Res. 2009;84:326-335. https://doi.org/10.1093/cvr/cvp220
  42. Tsai S, Hollenbeck ST, Ryer EJ, Edlin R, Yamanouchi D, Kundi R, Wang C, Liu B, Kent KC. TGF-beta through Smad3 signaling stimulates vascular smooth muscle cell proliferation and neointimal formation. Am J Physiol Heart Circ Physiol. 2009;297:H540-H549. https://doi.org/10.1152/ajpheart.91478.2007