{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T22:06:21Z","timestamp":1775945181683,"version":"3.50.1"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T00:00:00Z","timestamp":1633305600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Myocardin related transcription factors (MRTFs: MYOCD\/myocardin, MRTF-A, and MRTF-B) play a key role in smooth muscle cell differentiation by activating contractile genes. In atherosclerosis, MRTF levels change, and most notable is a fall of MYOCD. Previous work described anti-inflammatory properties of MRTF-A and MYOCD, occurring through RelA binding, suggesting that MYOCD reduction could contribute to vascular inflammation. Recent studies have muddled this picture showing that MRTFs may show both anti- and pro-inflammatory properties, but the basis of these discrepancies remain unclear. Moreover, the impact of MRTFs on inflammatory signaling pathways in tissues relevant to human arterial disease is uncertain. The current work aimed to address these issues. RNA-sequencing after forced expression of myocardin in human coronary artery smooth muscle cells (hCASMCs) showed reduction of pro-inflammatory transcripts, including <jats:italic>CCL2<\/jats:italic>, <jats:italic>CXCL8<\/jats:italic>, <jats:italic>IL6<\/jats:italic>, and <jats:italic>IL1B<\/jats:italic>. Side-by-side comparison of MYOCD, MRTF-A, and MRTF-B in hCASMCs, showed that the anti-inflammatory impact was shared among MRTFs. Correlation analyses using human arterial transcriptomic datasets revealed negative correlations between <jats:italic>MYOCD<\/jats:italic>, <jats:italic>MRTFA<\/jats:italic>, and <jats:italic>SRF<\/jats:italic>, on the one hand, and the inflammatory transcripts, on the other. A pro-inflammatory drive from lipopolysaccharide, did not change the size of the suppressive effect of MRTF-A in hCASMCs on either mRNA or protein levels. To examine cell type-dependence, we compared the anti-inflammatory impact in hCASMCs, with that in human bladder SMCs, in endothelial cells, and in monocytes (THP-1 cells). Surprisingly, little anti-inflammatory activity was seen in endothelial cells and monocytes, and in bladder SMCs, MRTF-A was pro-inflammatory. <jats:italic>CXCL8<\/jats:italic>, <jats:italic>IL6<\/jats:italic>, and <jats:italic>IL1B<\/jats:italic> were increased by the MRTF-SRF inhibitor CCG-1423 and by MRTF-A silencing in hCASMCs, but depolymerization of actin, known to inhibit MRTF activity, had no stimulatory effect, an exception being <jats:italic>IL1B<\/jats:italic>. Co-immunoprecipitation supported binding of MRTF-A to RelA, supporting sequestration of this important pro-inflammatory mediator as a mechanism. Dexamethasone treatment and silencing of RelA (by 76 \u00b1 1%) however only eliminated a fraction of the MRTF-A effect (\u224825%), suggesting mechanisms beyond RelA binding. Indeed, SRF silencing suggested that MRTF-A suppression of <jats:italic>IL1B<\/jats:italic> and <jats:italic>CXCL8<\/jats:italic> depends on SRF. This work thus supports an anti-inflammatory impact of MRTF-SRF signaling in hCASMCs and in intact human arteries, but not in several other cell types.<\/jats:p>","DOI":"10.3389\/fphys.2021.732564","type":"journal-article","created":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T05:58:45Z","timestamp":1633327125000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Cell Type Dependent Suppression of Inflammatory Mediators by Myocardin Related Transcription Factors"],"prefix":"10.3389","volume":"12","author":[{"given":"Li","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth","family":"Bankell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catarina","family":"Rippe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bj\u00f6rn","family":"Mor\u00e9n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin G.","family":"Stenkula","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bengt-Olof","family":"Nilsson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karl","family":"Sw\u00e4rd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1883","DOI":"10.1084\/jem.20060336","article-title":"Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1.","volume":"203","author":"Abraham","year":"2006","journal-title":"J. Exp. Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1161\/ATVBAHA.114.305218","article-title":"Myocardin regulates vascular smooth muscle cell inflammatory activation and disease.","volume":"35","author":"Ackers-Johnson","year":"2015","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"106837","DOI":"10.1016\/j.vph.2021.106837","article-title":"MRTFA overexpression promotes conversion of human coronary artery smooth muscle cells into lipid-laden foam cells.","volume":"138","author":"Alajbegovic","year":"2021","journal-title":"Vascul. Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1093\/cvr\/cvy022","article-title":"Smooth muscle cell fate and plasticity in atherosclerosis.","volume":"114","author":"Allahverdian","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"9273","DOI":"10.1074\/jbc.M109.075218","article-title":"Force-induced myofibroblast differentiation through collagen receptors is dependent on mammalian diaphanous (mDia).","volume":"285","author":"Chan","year":"2010","journal-title":"J. Biol. Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.mce.2007.04.013","article-title":"Anti-inflammatory functions of glucocorticoid-induced genes.","volume":"275","author":"Clark","year":"2007","journal-title":"Mol. Cell. Endocrinol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1038\/ng.2653","article-title":"The Genotype-Tissue Expression (GTEx) project.","volume":"45","author":"Consortium","year":"2013","journal-title":"Nat. Genet."},{"key":"B8","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1126\/science.1262110","article-title":"Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans.","volume":"348","author":"Consortium","year":"2015","journal-title":"Science"},{"key":"B9","doi-asserted-by":"publisher","first-page":"6333","DOI":"10.1038\/ncomms7333","article-title":"Cyclic stretching of soft substrates induces spreading and growth.","volume":"6","author":"Cui","year":"2015","journal-title":"Nat. Commun."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2249","DOI":"10.1158\/1535-7163.MCT-06-0782","article-title":"CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling.","volume":"6","author":"Evelyn","year":"2007","journal-title":"Mol. Cancer Ther."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2361","DOI":"10.1101\/gad.304501.117","article-title":"Mutual dependence of the MRTF-SRF and YAP-TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics.","volume":"31","author":"Foster","year":"2017","journal-title":"Genes Dev."},{"key":"B12","doi-asserted-by":"publisher","first-page":"101903","DOI":"10.1016\/j.redox.2021.101903","article-title":"MKL1 cooperates with p38MAPK to promote vascular senescence, inflammation, and abdominal aortic aneurysm.","volume":"41","author":"Gao","year":"2021","journal-title":"Redox Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1161\/CIRCRESAHA.119.315380","article-title":"Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke: meta-Analysis of Population-Based Studies Involving 17 180 Individuals.","volume":"125","author":"Georgakis","year":"2019","journal-title":"Circ. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"cvab046","DOI":"10.1093\/cvr\/cvab046","article-title":"Vascular smooth muscle cells in atherosclerosis:Time for a reassessment.","volume":"8","author":"Grootaert","year":"2021","journal-title":"Cardiovasc. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/S1097-2765(00)80139-2","article-title":"Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice.","volume":"2","author":"Gu","year":"1998","journal-title":"Mol. Cell."},{"key":"B16","doi-asserted-by":"publisher","first-page":"5647","DOI":"10.1073\/pnas.1618239114","article-title":"Stem cell migration and mechanotransduction on linear stiffness gradient hydrogels.","volume":"114","author":"Hadden","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e0229888","DOI":"10.1371\/journal.pone.0229888","article-title":"MRTF-A promotes angiotensin II-induced inflammatory response and aortic dissection in mice.","volume":"15","author":"Ito","year":"2020","journal-title":"PLoS One"},{"key":"B18","doi-asserted-by":"publisher","first-page":"11349","DOI":"10.1073\/pnas.1300801110","article-title":"Cell geometric constraints induce modular gene-expression patterns via redistribution of HDAC3 regulated by actomyosin contractility.","volume":"110","author":"Jain","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e0133931","DOI":"10.1371\/journal.pone.0133931","article-title":"Myocardin Family Members Drive Formation of Caveolae.","volume":"10","author":"Krawczyk","year":"2015","journal-title":"PLoS One"},{"key":"B20","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.lfs.2015.01.004","article-title":"Comparative effects of estrogen, raloxifene and tamoxifen on endothelial dysfunction, inflammatory markers and oxidative stress in ovariectomized rats.","volume":"124","author":"Lamas","year":"2015","journal-title":"Life Sci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1594","DOI":"10.1016\/j.jacc.2019.07.061","article-title":"From Focal Lipid Storage to Systemic Inflammation: jACC Review Topic of the Week.","volume":"74","author":"Libby","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.710968","article-title":"Regulation of the muscarinic m3 receptor by myocardin-related transcription factors.","volume":"12","author":"Liu","year":"2021","journal-title":"Front. Physiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1161\/CIRCULATIONAHA.105.543579","article-title":"CCL2 polymorphisms are associated with serum monocyte chemoattractant protein-1 levels and myocardial infarction in the Framingham Heart Study.","volume":"112","author":"McDermott","year":"2005","journal-title":"Circulation"},{"key":"B24","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1016\/j.cellsig.2006.09.004","article-title":"Sphingosine 1-phosphate phosphatase 2 is induced during inflammatory responses.","volume":"19","author":"Mechtcheriakova","year":"2007","journal-title":"Cell. Signal."},{"key":"B25","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/S0022-2828(03)00110-X","article-title":"Serum response factor: toggling between disparate programs of gene expression.","volume":"35","author":"Miano","year":"2003","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"3","DOI":"10.7555\/JBR.29.20140151","article-title":"Myocardin in biology and disease.","volume":"29","author":"Miano","year":"2015","journal-title":"J. Biomed. Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"4428","DOI":"10.1038\/emboj.2012.296","article-title":"Reciprocal expression of MRTF-A and myocardin is crucial for pathological vascular remodelling in mice.","volume":"31","author":"Minami","year":"2012","journal-title":"EMBO J."},{"key":"B28","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/S0092-8674(03)00278-2","article-title":"Actin dynamics control SRF activity by regulation of its coactivator MAL.","volume":"113","author":"Miralles","year":"2003","journal-title":"Cell"},{"key":"B29","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/nrm2890","article-title":"Linking actin dynamics and gene transcription to drive cellular motile functions.","volume":"11","author":"Olson","year":"2010","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1152\/physrev.00041.2003","article-title":"Molecular regulation of vascular smooth muscle cell differentiation in development and disease.","volume":"84","author":"Owens","year":"2004","journal-title":"Physiol. Rev."},{"key":"B31","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1161\/01.RES.0000259563.61091.e8","article-title":"Myocardin-related transcription factors: critical coactivators regulating cardiovascular development and adaptation.","volume":"100","author":"Parmacek","year":"2007","journal-title":"Circ. Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1056\/NEJMoa1707914","article-title":"Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease.","volume":"377","author":"Ridker","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1161\/01.ATV.0000255559.77687.c1","article-title":"Diaphanous 1 and 2 regulate smooth muscle cell differentiation by activating the myocardin-related transcription factors.","volume":"27","author":"Staus","year":"2007","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"C1128","DOI":"10.1152\/ajpcell.00047.2019","article-title":"Identification of the intermediate filament protein synemin\/SYNM as a target of myocardin family coactivators.","volume":"317","author":"Sward","year":"2019","journal-title":"Am. J. Physiol. Cell. Physiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"4741","DOI":"10.1113\/JP271913","article-title":"Emerging roles of the myocardin family of proteins in lipid and glucose metabolism.","volume":"594","author":"Sward","year":"2016","journal-title":"J. Physiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1093\/intimm\/dxy021","article-title":"Using genes to triangulate the pathophysiology of granulomatous autoinflammatory disease: nOD2, PLCG2 and LACC1.","volume":"30","author":"Szymanski","year":"2018","journal-title":"Int. Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"3362","DOI":"10.1073\/pnas.0705842105","article-title":"Myocardin inhibits cellular proliferation by inhibiting NF-kappaB(p65)-dependent cell cycle progression.","volume":"105","author":"Tang","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B38","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1111\/j.1432-0436.1984.tb01351.x","article-title":"Phenotype modulation in primary cultures of arterial smooth muscle cells. On the role of platelet-derived growth factor.","volume":"25","author":"Thyberg","year":"1983","journal-title":"Differentiation"},{"key":"B39","doi-asserted-by":"publisher","first-page":"28067","DOI":"10.1074\/jbc.M112.379487","article-title":"Bone morphogenetic protein signaling in vascular disease: anti-inflammatory action through myocardin-related transcription factor A.","volume":"287","author":"Wang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B40","doi-asserted-by":"publisher","first-page":"158824","DOI":"10.1016\/j.bbalip.2020.158824","article-title":"Myocardin suppression increases lipid retention and atherosclerosis via downregulation of ABCA1 in vascular smooth muscle cells.","volume":"1866","author":"Xia","year":"2021","journal-title":"Biochim. Biophys. Acta Mol. Cell. Biol. Lipids"},{"key":"B41","doi-asserted-by":"publisher","first-page":"10460","DOI":"10.1093\/nar\/gku776","article-title":"MRTF-A steers an epigenetic complex to activate endothelin-induced pro-inflammatory transcription in vascular smooth muscle cells.","volume":"42","author":"Yang","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"4645","DOI":"10.1242\/jcs.152314","article-title":"MRTF-A mediates LPS-induced pro-inflammatory transcription by interacting with the COMPASS complex.","volume":"127","author":"Yu","year":"2014","journal-title":"J. Cell. Sci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1242\/jcs.001586","article-title":"Force activates smooth muscle alpha-actin promoter activity through the Rho signaling pathway.","volume":"120","author":"Zhao","year":"2007","journal-title":"J. Cell. Sci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"e0176759","DOI":"10.1371\/journal.pone.0176759","article-title":"Similar regulatory mechanisms of caveolins and cavins by myocardin family coactivators in arterial and bladder smooth muscle.","volume":"12","author":"Zhu","year":"2017","journal-title":"PLoS One"}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.732564\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T05:58:48Z","timestamp":1633327128000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.732564\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,4]]},"references-count":44,"alternative-id":["10.3389\/fphys.2021.732564"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2021.732564","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,4]]},"article-number":"732564"}}