{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T22:34:22Z","timestamp":1776897262353,"version":"3.51.2"},"reference-count":36,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,5,11]],"date-time":"2024-05-11T00:00:00Z","timestamp":1715385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Scleroderma Foundation (GSB)","award":["S10RR027777"],"award-info":[{"award-number":["S10RR027777"]}]},{"name":"Scleroderma Foundation (GSB)","award":["NIH-NIGMS P30 GM103342"],"award-info":[{"award-number":["NIH-NIGMS P30 GM103342"]}]},{"name":"NIH National Center for Research Resources","award":["S10RR027777"],"award-info":[{"award-number":["S10RR027777"]}]},{"name":"NIH National Center for Research Resources","award":["NIH-NIGMS P30 GM103342"],"award-info":[{"award-number":["NIH-NIGMS P30 GM103342"]}]},{"name":"South Carolina COBRE for Developmentally Based Cardiovascular Diseases","award":["S10RR027777"],"award-info":[{"award-number":["S10RR027777"]}]},{"name":"South Carolina COBRE for Developmentally Based Cardiovascular Diseases","award":["NIH-NIGMS P30 GM103342"],"award-info":[{"award-number":["NIH-NIGMS P30 GM103342"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We previously found IQ motif containing GTPase activating protein (IQGAP1) to be consistently elevated in lung fibroblasts (LF) isolated from patients with scleroderma (systemic sclerosis, SSc)-associated interstitial lung disease (ILD) and reported that IQGAP1 contributed to SSc by regulating expression and organization of \u03b1-smooth muscle actin (SMA) in LF. The aim of this study was to compare the development of ILD in the presence and absence of IQGAP1. Pulmonary fibrosis was induced in IQGAP1 knockout (KO) and wild-type (WT) mice by a single-intratracheal instillation of bleomycin. Two and three weeks later, mice were euthanized and investigated. We observed that the IQGAP1 KO mouse was characterized by a reduced rate of actin polymerization with reduced accumulation of actin in the lung compared to the WT mouse. After exposure to bleomycin, the IQGAP1 KO mouse demonstrated decreased contractile activity of LF, reduced expression of SMA, TGF\u03b2, and collagen, and lowered overall fibrosis scores compared to the WT mouse. The numbers of inflammatory cells and expression of pro-inflammatory cytokines in lung tissue were not significantly different between IQGAP1 KO and WT mice. We conclude that IQGAP1 plays an important role in the development of lung fibrosis induced by bleomycin, and the absence of IQGAP1 reduces the contractile activity of lung fibroblast and bleomycin-induced pulmonary fibrosis. Thus, IQGAP1 may be a potential target for novel anti-fibrotic therapies for lung fibrosis.<\/jats:p>","DOI":"10.3390\/ijms25105244","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T08:03:08Z","timestamp":1715673788000},"page":"5244","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["IQGAP1 Regulates Actin Polymerization and Contributes to Bleomycin-Induced Lung Fibrosis"],"prefix":"10.3390","volume":"25","author":[{"given":"Tanjina","family":"Akter","sequence":"first","affiliation":[{"name":"Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 912, Charleston, SC 29425, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilia","family":"Atanelishvili","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 912, Charleston, SC 29425, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard M.","family":"Silver","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 912, Charleston, SC 29425, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Galina S.","family":"Bogatkevich","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 912, Charleston, SC 29425, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.tcb.2006.03.002","article-title":"IQGAP1 in cellular signaling: Bridging the GAP","volume":"16","author":"Brown","year":"2006","journal-title":"Trends Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.molimm.2015.02.012","article-title":"IQGAP1: Insights into the function of a molecular puppeteer","volume":"65","author":"Abel","year":"2015","journal-title":"Mol. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4347","DOI":"10.1074\/jbc.M208579200","article-title":"Elucidation of the interaction of calmodulin with the IQ motifs of IQGAP1","volume":"278","author":"Li","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1042\/BST0390694","article-title":"The interaction of IQGAPs with calmodulin-like proteins","volume":"39","author":"Pathmanathan","year":"2011","journal-title":"Biochem. Soc. Trans."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wang, H., Ramshekar, A., Cung, T., Wallace-Carrete, C., Zaugg, C., Nguyen, J., Stoddard, G.J., and Hartnett, M.E. (2023). 7-Ketocholesterol Promotes Retinal Pigment Epithelium Senescence and Fibrosis of Choroidal Neovascularization via IQGAP1 Phosphorylation-Dependent Signaling. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241210276"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.omtn.2021.12.020","article-title":"Silencing IQGAP1 alleviates hepatic fibrogenesis via blocking bone marrow mesenchymal stromal cell recruitment to fibrotic liver","volume":"27","author":"Ma","year":"2021","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"L603","DOI":"10.1152\/ajplung.00530.2007","article-title":"Proteomic analysis of CTGF-activated lung fibroblasts: Identification of IQGAP1 as a key player in lung fibroblast migration","volume":"295","author":"Bogatkevich","year":"2008","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_8","first-page":"242","article-title":"IQGAP1 Mediates \u03b1-Smooth Muscle Actin Expression and Enhances Contractility of Lung Fibroblasts","volume":"8","author":"Akter","year":"2018","journal-title":"Rheumatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/S0140-6736(17)30933-9","article-title":"Systemic sclerosis","volume":"390","author":"Denton","year":"2017","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ko, J., Noviani, M., Chellamuthu, V.R., Albani, S., and Low, A.H.L. (2023). The Pathogenesis of Systemic Sclerosis: The Origin of Fibrosis and Interlink with Vasculopathy and Autoimmunity. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241814287"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s12931-019-0980-7","article-title":"Interstitial lung disease associated with systemic sclerosis (SSc-ILD)","volume":"20","author":"Cottin","year":"2019","journal-title":"Respir. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1097\/MCP.0000000000000707","article-title":"Systemic sclerosis-associated interstitial lung disease","volume":"26","author":"Scallan","year":"2020","journal-title":"Curr. Opin. Pulm. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Mouawad, J.E., and Feghali-Bostwick, C. (2023). The Molecular Mechanisms of Systemic Sclerosis-Associated Lung Fibrosis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032963"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"L334","DOI":"10.1152\/ajplung.00417.2002","article-title":"Contractile activity and smooth muscle \u03b1-actin organization in thrombin-induced human lung myofibroblasts","volume":"285","author":"Bogatkevich","year":"2003","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/nrm809","article-title":"Myofibroblasts and mechano-regulation of connective tissue remodelling","volume":"3","author":"Tomasek","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1002\/jmri.25579","article-title":"Quantitative assessment of lung stiffness in patients with interstitial lung disease using MR elastography","volume":"46","author":"Marinelli","year":"2017","journal-title":"JMRI"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1097\/BOR.0000000000000331","article-title":"Animal models of scleroderma: Recent progress","volume":"28","author":"Marangoni","year":"2016","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1007\/s11926-015-0553-9","article-title":"Critical Appraisal of the Utility and Limitations of Animal Models of Scleroderma","volume":"18","author":"Tsujino","year":"2016","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1136\/jcp.41.4.467","article-title":"Simple method of estimating severity of pulmonary fibrosis on a numerical scale","volume":"41","author":"Ashcroft","year":"1988","journal-title":"J. Clin. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1002\/art.30255","article-title":"Anti-inflammatory and anti-fibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstitial lung disease","volume":"63","author":"Bogatkevich","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1006\/bbrc.1998.9371","article-title":"Binding of myosin essential light chain to the cytoskeleton-associated protein IQGAP1","volume":"251","author":"Weissbach","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1074\/jbc.M607711200","article-title":"IQGAP1 stimulates actin assembly through the N-WASP-Arp2\/3 pathway","volume":"282","author":"Schlaepfer","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1002\/cm.20013","article-title":"Actin filament binding by a monomeric IQGAP1 fragment with a single calponin homology domain","volume":"58","author":"Mateer","year":"2004","journal-title":"Cell Motil."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1021\/np010550q","article-title":"Cloning and characterization of the bleomycin biosynthetic gene cluster from Streptomyces verticillus ATCC15003","volume":"65","author":"Shen","year":"2002","journal-title":"J. Nat. Prod."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.pupt.2005.01.007","article-title":"Bleomycin lung toxicity: Who are the patients with increased risk?","volume":"18","author":"Azambuja","year":"2005","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1097\/MCP.0b013e328349ac2b","article-title":"Modeling pulmonary fibrosis with bleomycin","volume":"17","author":"Mouratis","year":"2011","journal-title":"Curr. Opin. Pulm. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1091\/mbc.E19-10-0554","article-title":"Flightless anchors IQGAP1 and R-ras to mediate cell extension formation and matrix remodeling","volume":"31","author":"Arora","year":"2020","journal-title":"Mol. Biol. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Urao, N., Razvi, M., Oshikawa, J., McKinney, R.D., Chavda, R., Bahou, W.F., Fukai, T., and Ushio-Fukai, M. (2010). IQGAP1 is involved in post-ischemic neovascularization by regulating angiogenesis and macrophage infiltration. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013440"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3975","DOI":"10.1038\/s41467-019-11606-x","article-title":"Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions","volume":"10","author":"Akula","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e22007","DOI":"10.1096\/fj.202101354","article-title":"IQGAP1-mediated mechanical signaling promotes the foreign body response to biomedical implants","volume":"36","author":"Sivaraj","year":"2022","journal-title":"FASEB J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1096\/fj.201900879RR","article-title":"IQGAP1 restrains T-cell cosignaling mediated by OX40","volume":"34","author":"Okuyama","year":"2020","journal-title":"FASEB J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.2353\/ajpath.2007.070112","article-title":"The myofibroblast: One function, multiple origins","volume":"170","author":"Hinz","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/S0955-0674(05)80007-9","article-title":"Actin isoforms","volume":"5","author":"Herman","year":"1993","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0074-7696(01)02003-4","article-title":"Functional specificity of actin isoforms","volume":"202","author":"Khaitlina","year":"2001","journal-title":"Int. Rev. Cyt."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1128\/MCB.20.2.697-701.2000","article-title":"Gastric hyperplasia in mice lacking the putative Cdc42 effector IQGAP1","volume":"20","author":"Li","year":"2000","journal-title":"Mol. Cell. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT\u2013PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/10\/5244\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:44:20Z","timestamp":1760107460000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/10\/5244"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,11]]},"references-count":36,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["ijms25105244"],"URL":"https:\/\/doi.org\/10.3390\/ijms25105244","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,11]]}}}