{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T02:50:58Z","timestamp":1772506258837,"version":"3.50.1"},"reference-count":37,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,30]],"date-time":"2021-10-30T00:00:00Z","timestamp":1635552000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","award":["CVON-PREDICT"],"award-info":[{"award-number":["CVON-PREDICT"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Medical Research Council of Singapore","award":["CS-IRG13nov024"],"award-info":[{"award-number":["CS-IRG13nov024"]}]},{"name":"ATTRaCT grant","award":["SPF2014\/003"],"award-info":[{"award-number":["SPF2014\/003"]}]},{"DOI":"10.13039\/501100001722","name":"Royal Netherlands Academy of Arts and Sciences","doi-asserted-by":"publisher","award":["Strategic grant"],"award-info":[{"award-number":["Strategic grant"]}],"id":[{"id":"10.13039\/501100001722","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National University Health System collaborative grant","award":["NUHS O-CRG"],"award-info":[{"award-number":["NUHS O-CRG"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Involvement of the Toll-like receptor 4 (TLR4) in maladaptive cardiac remodeling and heart failure (HF) upon pressure overload has been studied extensively, but less is known about the role of TLR2. Interplay and redundancy of TLR4 with TLR2 have been reported in other organs but were not investigated during cardiac dysfunction. We explored whether TLR2 deficiency leads to less adverse cardiac remodeling upon chronic pressure overload and whether TLR2 and TLR4 additively contribute to this. We subjected 35 male C57BL\/6J mice (wildtype (WT) or TLR2 knockout (KO)) to sham or transverse aortic constriction (TAC) surgery. After 12 weeks, echocardiography and electrocardiography were performed, and hearts were extracted for molecular and histological analysis. TLR2 deficiency (n = 14) was confirmed in all KO mice by PCR and resulted in less hypertrophy (heart weight to tibia length ratio (HW\/TL), smaller cross-sectional cardiomyocyte area and decreased brain natriuretic peptide (BNP) mRNA expression, p &lt; 0.05), increased contractility (QRS and QTc, p &lt; 0.05), and less inflammation (e.g., interleukins 6 and 1\u03b2, p &lt; 0.05) after TAC compared to WT animals (n = 11). Even though TLR2 KO TAC animals presented with lower levels of ventricular TLR4 mRNA than WT TAC animals (13.2 \u00b1 0.8 vs. 16.6 \u00b1 0.7 mg\/mm, p &lt; 0.01), TLR4 mRNA expression was increased in animals with the largest ventricular mass, highest hypertrophy, and lowest ejection fraction, leading to two distinct groups of TLR2 KO TAC animals with variations in cardiac remodeling. This variation, however, was not seen in WT TAC animals even though heart weight\/tibia length correlated with expression of TLR4 in these animals (r = 0.078, p = 0.005). Our data suggest that TLR2 deficiency ameliorates adverse cardiac remodeling and that ventricular TLR2 and TLR4 additively contribute to adverse cardiac remodeling during chronic pressure overload. Therefore, both TLRs may be therapeutic targets to prevent or interfere in the underlying molecular processes.<\/jats:p>","DOI":"10.3390\/ijms222111823","type":"journal-article","created":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T22:21:34Z","timestamp":1635805294000},"page":"11823","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Ventricular TLR4 Levels Abrogate TLR2-Mediated Adverse Cardiac Remodeling upon Pressure Overload in Mice"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1974-4571","authenticated-orcid":false,"given":"Elise L.","family":"Kessler","sequence":"first","affiliation":[{"name":"Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3584CM Utrecht, The Netherlands"},{"name":"Laboratory Experimental Cardiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3508GA Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7986-6082","authenticated-orcid":false,"given":"Jiong-Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore 117597, Singapore"},{"name":"Cardiovascular Research Institute, National University Heart Centre Singapore, Singapore 117599, Singapore"},{"name":"Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore 117597, Singapore"},{"name":"Nanomedicine Translational Research Programme, Centre for NanoMedicine, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore 117597, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bart","family":"Kok","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3584CM Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maike A.","family":"Brans","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3584CM Utrecht, The Netherlands"},{"name":"Laboratory Experimental Cardiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3508GA Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelique","family":"Nederlof","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3584CM Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonie","family":"van Stuijvenberg","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3584CM Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenyuan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore 117597, Singapore"},{"name":"Cardiovascular Research Institute, National University Heart Centre Singapore, Singapore 117599, Singapore"},{"name":"Nanomedicine Translational Research Programme, Centre for NanoMedicine, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore 117597, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aryan","family":"Vink","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Medical Center Utrecht, 3508GA Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6598-8599","authenticated-orcid":false,"given":"Fatih","family":"Arslan","sequence":"additional","affiliation":[{"name":"Laboratory Experimental Cardiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3508GA Utrecht, The Netherlands"},{"name":"Department of Cardiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3508GA Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor R.","family":"Efimov","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, George Washington University, Washington, DC 20052, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolyn S. P.","family":"Lam","sequence":"additional","affiliation":[{"name":"National Heart Centre Singapore and Duke-National University of Singapore, 5 Hospital Dr, Singapore 169609, Singapore"},{"name":"UMC Groningen, Hanzeplein 1, 9713GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc A.","family":"Vos","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3584CM Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominique P. V.","family":"de Kleijn","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, The Netherlands & Netherlands Heart Institute, University Medical Center Utrecht, Utrecht University, 3508GA Utrecht, The Netherlands"},{"name":"The Netherlands Heart Institute, Moreelsepark 1, 3511EP Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magda S. C.","family":"Fontes","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3584CM Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toon A. B.","family":"van Veen","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht University, 3584CM Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1093\/eurheartj\/ehw128","article-title":"2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure","volume":"37","author":"Ponikowski","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1161\/CIR.0000000000000366","article-title":"Executive summary: Heart disease and stroke statistics-2016 update: A Report from the American Heart Association","volume":"133","author":"Mozaffarian","year":"2016","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1152\/physrev.1999.79.1.215","article-title":"Molecular Mechanisms of Myocardial Remodeling","volume":"79","author":"Swynghedauw","year":"1999","journal-title":"Physiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1161\/CIRCRESAHA.116.308030","article-title":"Chronic Heart Failure and Inflammation: What Do We Really Know?","volume":"119","author":"Dick","year":"2016","journal-title":"Circ. Res."},{"key":"ref_5","first-page":"1","article-title":"The Role of Toll-Like Receptor Signaling in the Progression of Heart Failure","volume":"2018","author":"Yu","year":"2018","journal-title":"Mediat. Inflamm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.str.2011.02.004","article-title":"The Structural Biology of Toll-like Receptors","volume":"19","author":"Botos","year":"2011","journal-title":"Structure"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1161\/CIRCRESAHA.110.226936","article-title":"The Emerging Role of Innate Immunity in the Heart and Vascular System","volume":"108","author":"Mann","year":"2011","journal-title":"Circ. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"461","DOI":"10.3389\/fimmu.2014.00461","article-title":"Toll-Like Receptor Signaling Pathways","volume":"5","author":"Kawasaki","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1161\/CIRCULATIONAHA.109.880187","article-title":"Myocardial Ischemia\/Reperfusion Injury Is Mediated by Leukocytic Toll-Like Receptor-2 and Reduced by Systemic Administration of a Novel Anti\u2013Toll-Like Receptor-2 Antibody","volume":"121","author":"Arslan","year":"2010","journal-title":"Circulation"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.1161\/01.CIR.0000101921.93016.1C","article-title":"Toll-Like Receptor-2 Modulates Ventricular Remodeling After Myocardial Infarction","volume":"108","author":"Shishido","year":"2003","journal-title":"Circulation"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1093\/cvr\/cvt258","article-title":"Inhibition of Toll-like receptor 2 reduces cardiac fibrosis by attenuating macrophage-mediated inflammation","volume":"101","author":"Wang","year":"2013","journal-title":"Cardiovasc. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2654","DOI":"10.1161\/CIRCULATIONAHA.104.498865","article-title":"Expansion of Circulating Toll-Like Receptor 4\u2013Positive Monocytes in Patients With Acute Coronary Syndrome","volume":"111","author":"Methe","year":"2005","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1536\/ihj.17-084","article-title":"Toll-Like Receptors 2 and 4 Predict New-Onset Atrial Fibrillation in Acute Myocardial Infarction Patients","volume":"59","author":"Zhang","year":"2018","journal-title":"Int. Heart J."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Avlas, O., Bragg, A., Fuks, A., Nicholson, J.D., Farkash, A., Porat, E., Aravot, D., Levy-Drummer, R.S., Cohen, C., and Shainberg, A. (2015). TLR4 Expression Is Associated with Left Ventricular Dysfunction in Patients Undergoing Coronary Artery Bypass Surgery. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0120175"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2728","DOI":"10.1111\/jcmm.12659","article-title":"Up-regulated TLR 4 in cardiomyocytes exacerbates heart failure after long-term myocardial infarction","volume":"19","author":"Liu","year":"2015","journal-title":"J. Cell. Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1093\/eurjhf\/hfr035","article-title":"The toll-like receptor 4-antagonist eritoran reduces murine cardiac hypertrophy","volume":"13","author":"Ehrentraut","year":"2011","journal-title":"Eur. J. Heart Fail."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1161\/CIRCRESAHA.107.158220","article-title":"Toll-Like Receptor 4 Mediates Maladaptive Left Ventricular Remodeling and Impairs Cardiac Function After Myocardial Infarction","volume":"102","author":"Timmers","year":"2008","journal-title":"Circ. Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ehrentraut, H., Ehrentraut, S., Boehm, O., El Aissati, S., Foltz, F., Goelz, L., Goertz, D., Kebir, S., Weisheit, C., and Wolf, M. (2015). Tlr4 Deficiency Protects against Cardiac Pressure Overload Induced Hyperinflammation. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0142921"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1096\/fj.05-5133fje","article-title":"Absence of NF-\u03baB subunit p50 improves heart failure after myocardial infarction","volume":"20","author":"Frantz","year":"2006","journal-title":"FASEB J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"H1089","DOI":"10.1152\/ajpheart.00067.2013","article-title":"Cardiomyocyte-specific p65 NF-\u03baB deletion protects the injured heart by preservation of calcium handling","volume":"305","author":"Zhang","year":"2013","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.yjmcc.2010.08.006","article-title":"Arteriogenesis requires toll-like receptor 2 and 4 expression in bone-marrow derived cells","volume":"50","author":"Hoefer","year":"2011","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1002\/ana.24159","article-title":"Toll-like receptor 2\/4 heterodimer mediates inflammatory injury in intracerebral hemorrhage","volume":"75","author":"Wang","year":"2014","journal-title":"Ann. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1177\/1074248414539564","article-title":"Toll-Like Receptor 4 Knockout Protects Against Isoproterenol-Induced Cardiac Fibrosis: The role of autophagy","volume":"20","author":"Dong","year":"2015","journal-title":"J. Cardiovasc. Pharmacol. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"13073","DOI":"10.1074\/jbc.RA118.001880","article-title":"Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice","volume":"293","author":"Spurthi","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.4049\/jimmunol.166.3.2018","article-title":"Bacterial Lipopolysaccharide and IFN-\u03b3 Induce Toll-Like Receptor 2 and Toll-Like Receptor 4 Expression in Human Endothelial Cells: Role of NF-\u03baB Activation","volume":"166","author":"Faure","year":"2001","journal-title":"J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6924","DOI":"10.4049\/jimmunol.167.12.6924","article-title":"NF\u03baB and Sp1 Elements Are Necessary for Maximal Transcription of Toll-like Receptor 2 Induced byMycobacterium avium","volume":"167","author":"Wang","year":"2001","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"31197","DOI":"10.1074\/jbc.M705151200","article-title":"Microbial Products Stimulate Human Toll-like Receptor 2 Expression through Histone Modification Surrounding a Proximal NF-\u03baB-binding Site","volume":"282","author":"Johnson","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s12952-016-0050-3","article-title":"Tlr2 deficiency does not limit the development of left ventricular hypertrophy in a model of transverse aortic constriction induced pressure overload","volume":"15","author":"Bualeong","year":"2016","journal-title":"J. Negat. Results Biomed."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4223","DOI":"10.1038\/emboj.2010.268","article-title":"FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages","volume":"29","author":"Fan","year":"2010","journal-title":"EMBO J."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ma, Y., Zhang, X., Bao, H., Mi, S., Cai, W., Yan, H., Wang, Q., Wang, Z., Yan, J., and Fan, G. (2012). Toll-Like Receptor (TLR) 2 and TLR4 Differentially Regulate Doxorubicin Induced Cardiomyopathy in Mice. PLoS ONE, 7.","DOI":"10.1371\/annotation\/e82f77a8-3d29-44be-a9ef-7abc6c7e584a"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/S1053-2498(03)00106-2","article-title":"Increased toll-like receptor 4 in the myocardium of patients requiring left ventricular assist devices","volume":"23","author":"Birks","year":"2004","journal-title":"J. Heart Lung Transplant."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"20208","DOI":"10.1074\/jbc.M111.336255","article-title":"Toll-like Receptor 2 Is Required for LPS-induced Toll-like Receptor 4 Signaling and Inhibition of Ion Transport in Renal Thick Ascending Limb","volume":"287","author":"Good","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1097\/SHK.0b013e318186262d","article-title":"Role of toll-like receptors 2 and 4, and the receptor for advanced glycation end products in high-mobility group box 1-induced inflammation in vivo","volume":"31","author":"Yang","year":"2009","journal-title":"Shock"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1093\/eurjhf\/hfq092","article-title":"Heterogeneous Connexin43 distribution in heart failure is associated with dispersed conduction and enhanced susceptibility to ventricular arrhythmias","volume":"12","author":"Boulaksil","year":"2010","journal-title":"Eur. J. Heart Fail."},{"key":"ref_35","first-page":"1","article-title":"Leukocytic Toll-Like Receptor 2 Deficiency Preserves Cardiac Function And Reduces Fibrosis In Sustained Pressure Overload","volume":"7","author":"Wang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Fontes, M.S.C., Raaijmakers, A.J.A., Van Doorn, T., Kok, B., Nieuwenhuis, S., Van Der Nagel, R., Vos, M.A., De Boer, T.P., van Rijen, H., and Bierhuizen, M.F.A. (2014). Changes in Cx43 and NaV1.5 Expression Precede the Occurrence of Substantial Fibrosis in Calcineurin-Induced Murine Cardiac Hypertrophy. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087226"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"475","DOI":"10.7150\/ijbs.6.475","article-title":"Smaller cardiac cell size and reduced extra-cellular collagen might be beneficial for hearts of Ames dwarf mice","volume":"6","author":"Helms","year":"2010","journal-title":"Int. J. Biol. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11823\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:23:43Z","timestamp":1760167423000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11823"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,30]]},"references-count":37,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222111823"],"URL":"https:\/\/doi.org\/10.3390\/ijms222111823","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,30]]}}}