{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T13:04:15Z","timestamp":1781787855427,"version":"3.54.5"},"reference-count":36,"publisher":"Institute of Physiology of the Czech Academy of Sciences","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Physiol Res"],"abstract":"<jats:p>The proliferation and migration of vascular smooth muscle cells (VSMCs) are the initial contributors to restenosis in patients undergoing percutaneous coronary intervention (PCI). MicroRNA-145 (miR-145) plays a significant role in this pathological process. Although carvedilol has been shown to inhibit VSMC proliferation and migration, the underlying mechanisms are not fully understood. The aim of our study is to examine whether carvedilol regulates the expression of miR-145 and thereby inhibits the proliferation and migrative capacity of VSMCs. VSMCs were cultured and transfected with either miR-145 mimics or miR-145 inhibitors. Cell proliferation was evaluated using the Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2\u2032-deoxyuridine (EdU) assays, while wound healing and Transwell assays were used to assess the migration capacity. Protein expression levels were quantified using western blot analysis, and additionally, a luciferase reporter assay was performed to identify the target gene of miR-145. We found that carvedilol upregulated the expression of miR-145 and decreased the expression of Kr\u00fcppel-like factor 4 (KLF4). Furthermore, miR-145 inhibited VSMC proliferation and migration. KLF4 was identified as a direct target of miR-145. Importantly, the inhibition of miR-145 attenuated the suppressive effects of carvedilol on VSMCs. In summary, our results in this study demonstrate that carvedilol exerts its inhibitory effects on VSMC proliferation and migration, at least in part, through the upregulation of miR-145. These findings suggest that miR-145 may be a key mediator in the therapeutic effects of carvedilol on VSMCs.<\/jats:p>","DOI":"10.33549\/physiolres.935564","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T09:10:29Z","timestamp":1756717829000},"page":"577-588","source":"Crossref","is-referenced-by-count":1,"title":["Role of Carvedilol in Inhibiting the Proliferation and Migration of Vascular Smooth Muscle Cells by Upregulating microRNA-145 Expression"],"prefix":"10.33549","author":[{"given":"G","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Q","family":"Han","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Shanxi Medical University, Taiyuan, China, qinghuahanhqh@126.com"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"19169","published-online":{"date-parts":[[2025,8,31]]},"reference":[{"key":"ref0","doi-asserted-by":"publisher","unstructured":"Alfonso F, Coughlan JC, Giacoppo D, Kastrati A, Byrne RB. Management of in-stent restenosis. EuroIntervention 2022;18: e103-e123. https:\/\/doi.org\/10.4244\/EIJ-D-21-01034","DOI":"10.4244\/eij-d-21-01034"},{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Giustino G, Colombo A, Camaj A, Yasumura K, Mehran R, Stone GW, Kini A, Sharma SK. Coronary in-stent restenosis: JACC state-of-the-art review. J Am Coll Cardiol 2022;80:348-372. https:\/\/doi.org\/10.1016\/j.jacc.2022.05.017","DOI":"10.1016\/j.jacc.2022.05.017"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Yang X, Yang Y, J. Guo, Y. Meng, M. Li,  Yang, X. Liu, L.H.H. Aung, T. Yu, and Y. Li, Targeting the epigenome in in-stent restenosis: from mechanisms to therapy. Molecular Therapy - Nucleic Acids 2021;23: 1136-1160. https:\/\/doi.org\/10.1016\/j.omtn.2021.01.024","DOI":"10.1016\/j.omtn.2021.01.024"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev. 2004 Jul;84(3):767-801. https:\/\/doi.org\/10.1152\/physrev.00041.2003","DOI":"10.1152\/physrev.00041.2003"},{"key":"ref4","doi-asserted-by":"crossref","unstructured":"Schaer GL, Zhang C. Implementation of miRNAs to reduce in-stent restenosis in the future. J Am Coll Cardiol. 2015;65:2328-2330. https:\/\/doi.org\/10.1016\/j.jacc.2015.04.008","DOI":"10.1016\/j.jacc.2015.04.008"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Gareri C, De Rosa S, Indolfi C. MicroRNAs for restenosis and thrombosis after vascular injury. Circ Res 2016;118: 1170-1184. https:\/\/doi.org\/10.1161\/CIRCRESAHA.115.308237","DOI":"10.1161\/circresaha.115.308237"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"Stellos K, Dimmeler S. Vascular MicroRNAs. Circ Res 2014;114:3-4. https:\/\/doi.org\/10.1161\/CIRCRESAHA.113.302762","DOI":"10.1161\/CIRCRESAHA.113.302762"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Cheng Y, Liu X, Yang J, Lin Y, Xu D-Z, Lu Q, Deitch EA, Huo Y, Delphin ES, Zhang C. MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation. Circ Res 2009;105:158-166. https:\/\/doi.org\/10.1161\/CIRCRESAHA.109.197517","DOI":"10.1161\/circresaha.109.197517"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"Cordes KR, Sheehy NT, White MP, Berry EC, Morton SU, Muth AN, Lee TH, Miano JM, Ivey KN, Srivastava D. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature 2009;460:705-710. https:\/\/doi.org\/10.1038\/nature08195","DOI":"10.1038\/nature08195"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"Chin DD, Poon C, Wang J, Joo J, Ong V, Jiang Z, Cheng K, Plotkin A, Magee GA, Chung EJ. miR-145 micelles mitigate atherosclerosis by modulating vascular smooth muscle cell phenotype. Biomaterials  2021;273:120810. https:\/\/doi.org\/10.1016\/j.biomaterials.2021.120810","DOI":"10.1016\/j.biomaterials.2021.120810"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, et al. ACC\/AHA Joint Committee Members. 2022 AHA\/ACC\/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022 May 3;145(18):e895-e1032. Epub 2022 Apr 1. Erratum in: Circulation. 2022 May 3;145(18):e1033. https:\/\/doi.org\/10.1016\/j.jacc.2021.12.012","DOI":"10.1161\/cir.0000000000001073"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Ohlstein EH, Douglas SA, Sung CP, Yue TL, Louden C, Arleth A, Poste G, Ruffolo RR Jr, Feuerstein GZ. Carvedilol, a cardiovascular drug, prevents vascular smooth muscle cell proliferation, migration, and neointimal formation following vascular injury. Proc Natl Acad Sci U S A. 1993;90:6189-6193. https:\/\/doi.org\/10.1073\/pnas.90.13.6189","DOI":"10.1073\/pnas.90.13.6189"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Kim W, Jeong MH, Cha KS, Hyun DW, Hur SH, Kim KB et al. Effect of anti-oxidant (carvedilol and probucol) loaded stents in a porcine coronary restenosis model. Circ J 2005;69:101-106. https:\/\/doi.org\/10.1253\/circj.69.101","DOI":"10.1253\/circj.69.101"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Kim, I.-m., Y. Wang, K.-m. Park, Y. Tang, J.- Teoh, J. Vinson, C.J. Traynham, G. Pironti, L. Mao, H. Su, J.A. Johnson, W.J. Koch, and H.A. Rockman, \u03b2-Arrestin1-Biased \u03b21-Adrenergic Receptor Signaling Regulates MicroRNA Processing. Circulation Research, 2014. 114(5):  833-844. https:\/\/doi.org\/10.1161\/CIRCRESAHA.114.302766","DOI":"10.1161\/circresaha.114.302766"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Peng H, Wang J, Li S. MiR-15a-5p accelerated vascular smooth muscle cells viabilities and migratory abilities via targeting Bcl-2. Physiol Res. 2022 Nov 28;71(5):667-675. https:\/\/doi.org\/10.33549\/physiolres.934914","DOI":"10.33549\/physiolres.934914"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Liang J, Chu H, Ran Y, Lin R, Cai Y, Guan X, Cui X, Zhang X, Li H, Cheng M. Linc-ROR modulates the endothelial-mesenchymal transition of endothelial progenitor cells through the miR-145\/Smad3 signaling pathway. Physiol Res 2024;73:565-576. https:\/\/doi.org\/10.33549\/physiolres.935303","DOI":"10.33549\/physiolres.935303"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Wen, J., B. Tang, L. Guo, W. Chen, X. Tang, and T. Katsuya, miR-145 Alleviates Smooth Muscle Cell Phenotype Transition via ADAM17-Mediated ACE2 Shedding. International Journal of Hypertension, 2023. 2023:  1-14. https:\/\/doi.org\/10.1155\/2023\/9497716","DOI":"10.1155\/2023\/9497716"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Shahrokhi SZ, Saeidi L, Sadatamini M, Jafarzadeh M, Rahimipour A, Kazerouni F. Can miR-145-5p be used as a marker in diabetic patients? Arch Physiol Biochem 2022;128:1175-1180.  https:\/\/doi.org\/10.1080\/13813455.2020.1762657","DOI":"10.1080\/13813455.2020.1762657"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"He M, Gong Y, Shi J, Pan Z, Zou H, Sun D, Tu X, Tan X, Li J, Li W, Liu B, Xue J, Sheng L, Xiu C, Yang N, Xue H, Ding X, Yu C, Li Y. Plasma microRNAs as potential noninvasive biomarkers for in-stent restenosis. PLoS One. 2014;9:e112043.  https:\/\/doi.org\/10.1371\/journal.pone.0112043","DOI":"10.1371\/journal.pone.0112043"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Elia L, Quintavalle M, Zhang J, Contu R, Cossu L, Latronico MV, Peterson KL, Indolfi C, Catalucci D, Chen J, Courtneidge SA, Condorelli G. The knockout of miR-143 and -145 alters smooth muscle cell maintenance and vascular homeostasis in mice: correlates with human disease. Cell Death Differ 2009;16: 1590-1598. https:\/\/doi.org\/10.1038\/cdd.2009.153","DOI":"10.1038\/cdd.2009.153"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Wang W, Chen L, Shang C, Jin Z, Yao F, Bai L, Wang R, Zhao S, Liu E. miR-145 inhibits the proliferation and migration of vascular smooth muscle cells by regulating autophagy. J Cell Mol Med 2020;24:6658-6669. https:\/\/doi.org\/10.1111\/jcmm.15316","DOI":"10.1111\/jcmm.15316"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Yang W, Yin R, Zhu X, Yang S, Wang J, Zhou Z, Pan X, Ma A. Mesenchymal stem-cell-derived exosomal miR-145 inhibits atherosclerosis by targeting JAM-A. Mol Ther Nucleic Acids 2020;23:119-131. https:\/\/doi.org\/10.1016\/j.omtn.2020.10.037","DOI":"10.1016\/j.omtn.2020.10.037"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Zhang X, Zai L, Tao Z, Wu D, Lin M, Wan J. miR-145-5p affects autophagy by targeting CaMKII\u03b4 in atherosclerosis. Int J Cardiol 2022;360:68-75. https:\/\/doi.org\/10.1016\/j.ijcard.2022.05.039","DOI":"10.1016\/j.ijcard.2022.05.039"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Bieker JJ. Kr\u00fcppel-like factors: three fingers in many pies. J Biol Chem 2001;276:34355-34358.  https:\/\/doi.org\/10.1074\/jbc.R100043200","DOI":"10.1074\/jbc.r100043200"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Garvey SM, Sinden DS, Schoppee Bortz PD, Wamhoff BR. Cyclosporine up-regulates Kr\u00fcppel-like factor-4 (KLF4) in vascular smooth muscle cells and drives phenotypic modulation in vivo. J Pharmacol Exp Ther 2010;333:34-42. https:\/\/doi.org\/10.1124\/jpet.109.163949","DOI":"10.1124\/jpet.109.163949"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Wang C, Han M, Zhao XM, Wen JK. Kruppel-like factor 4 is required for the expression of vascular smooth muscle cell differentiation marker genes induced by all-trans retinoic acid. J Biochem 2008;144:313-321. https:\/\/doi.org\/10.1093\/jb\/mvn068","DOI":"10.1093\/jb\/mvn068"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Li HX, Han M, Bernier M, Zheng B, Sun SG, Su M, Zhang R, Fu JR, Wen JK. Kr\u00fcppel-like factor 4 promotes differentiation by transforming growth factor-beta receptor-mediated Smad and p38 MAPK signaling in vascular smooth muscle cells. J Biol Chem. 2010;285:17846-17856. https:\/\/doi.org\/10.1074\/jbc.M109.076992","DOI":"10.1074\/jbc.m109.076992"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Yap C, Mieremet A, de Vries CJM, Micha D, de Waard V. Six Shades of Vascular Smooth Muscle Cells Illuminated by KLF4 (Kr\u00fcppel-Like Factor 4). Arterioscler Thromb Vasc Biol 2021;41:2693-2707. https:\/\/doi.org\/10.1161\/ATVBAHA.121.316600","DOI":"10.1161\/atvbaha.121.316600"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Park J, Ha H, Kim MS, Ahn HJ, Huh KH, Kim YS. Carvedilol inhibits platelet-derived growth factor-induced extracellular matrix synthesis by inhibiting cellular reactive oxygen species and mitogen-activated protein kinase activation. J Heart Lung Transplant. 2006;25:683-689. https:\/\/doi.org\/10.1016\/j.healun.2006.01.008","DOI":"10.1016\/j.healun.2006.01.008"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Suzuki Y, Tanaka M, Sohmiya M, Yoshida T, Okamoto K. Antioxidant properties of carvedilol: inhibition of lipid peroxidation, protein oxidation and superoxide generation. Neurol Res. 2003;25:749-753. https:\/\/doi.org\/10.1179\/016164103101202110","DOI":"10.1179\/016164103101202110"},{"key":"ref30","doi-asserted-by":"crossref","unstructured":"Nakajima T, Ma J, Iida H, Iwasawa K, Jo T, Omata M, Nagai R. Inhibitory effects of carvedilol on calcium channels in vascular smooth muscle cells. Jpn Heart J 2003;44:963-978. https:\/\/doi.org\/10.1536\/jhj.44.963","DOI":"10.1536\/jhj.44.963"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Tseng YH, Liu CY, Lee CP, Lin MH, Yang YH. Effect of carvedilol on arteriovenous graft primary patency. Vascular 2020;28:765-774. https:\/\/doi.org\/10.1177\/1708538120923886","DOI":"10.1177\/1708538120923886"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Kent OA, Fox-Talbot K, Halushka MK. RREB1 repressed miR-143\/145 modulates KRAS signaling through downregulation of multiple targets. Oncogene 2013;32:2576-2585. https:\/\/doi.org\/10.1038\/onc.2012.266","DOI":"10.1038\/onc.2012.266"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Noguchi S, Yasui Y, Iwasaki J, Kumazaki M, Yamada N, Naito S, Akao Y. Replacement treatment with microRNA-143 and -145 induces synergistic inhibition of the growth of human bladder cancer cells by regulating PI3K\/Akt and MAPK signaling pathways. Cancer Lett 2013;328:353-361. https:\/\/doi.org\/10.1016\/j.canlet.2012.10.017","DOI":"10.1016\/j.canlet.2012.10.017"},{"key":"ref34","doi-asserted-by":"crossref","unstructured":"Bayoumi AS, Park KM, Wang Y, Teoh JP, Aonuma T, Tang Y, Su H, Weintraub NL, Kim IM. A carvedilol-responsive microRNA, miR-125b-5p protects the heart from acute myocardial infarction by repressing pro-apoptotic bak1 and klf13 in cardiomyocytes. J Mol Cell Cardiol 2018;114:72-82. https:\/\/doi.org\/10.1016\/j.yjmcc.2017.11.003","DOI":"10.1016\/j.yjmcc.2017.11.003"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Hu Y, Chen X, Li X, Li Z, Diao H, Liu L, Zhang J, Ju J, Wen L, Liu X, Pan Z, Xu C, Hai X, Zhang Y. MicroRNA\u20111 downregulation induced by carvedilol protects cardiomyocytes against apoptosis by targeting heat shock protein 60. Mol Med Rep 2019;19:3527-3536. https:\/\/doi.org\/10.3892\/mmr.2019.10034","DOI":"10.3892\/mmr.2019.10034"}],"container-title":["Physiological Research"],"original-title":[],"language":"en","deposited":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T09:10:32Z","timestamp":1756717832000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.biomed.cas.cz\/physiolres\/pdf\/2025\/74_577.pdf"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,31]]},"references-count":36,"URL":"https:\/\/doi.org\/10.33549\/physiolres.935564","relation":{},"ISSN":["1802-9973","0862-8408"],"issn-type":[{"value":"1802-9973","type":"electronic"},{"value":"0862-8408","type":"print"}],"subject":[],"published":{"date-parts":[[2025,8,31]]}}}