{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:12:42Z","timestamp":1791317562219,"version":"4.3.1"},"reference-count":41,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T00:00:00Z","timestamp":1702857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Outstanding Research Start-up Fund of Jining Medical University","award":["600791001P"],"award-info":[{"award-number":["600791001P"]}]},{"name":"Outstanding Research Start-up Fund of Jining Medical University","award":["KYCX20_0690"],"award-info":[{"award-number":["KYCX20_0690"]}]},{"name":"Postgraduate Research &amp; Practice Innovation Program of Jiangsu Province","award":["600791001P"],"award-info":[{"award-number":["600791001P"]}]},{"name":"Postgraduate Research &amp; Practice Innovation Program of Jiangsu Province","award":["KYCX20_0690"],"award-info":[{"award-number":["KYCX20_0690"]}]},{"name":"\u2018The Program of Exploring World\u2019 Student Scholarship of China Pharmaceutical University","award":["600791001P"],"award-info":[{"award-number":["600791001P"]}]},{"name":"\u2018The Program of Exploring World\u2019 Student Scholarship of China Pharmaceutical University","award":["KYCX20_0690"],"award-info":[{"award-number":["KYCX20_0690"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Aim: The impact of myocardial stressors such as high-fat diet (HFD) and pressure overload has been extensively studied. Toll-like receptor 4 (TLR4) deficiency has been suggested to have a protective role in response to these stressors, although some conflicting data exist. Furthermore, there is limited information about the role of TLR4 on cardiac remodeling in response to long-term exposure to stressors. This study aims to investigate the effects of TLR4 deficiency on cardiac histology and physiology in response to chronic stressors. Methods: TLR4-deficient (TLR4\u2212\/\u2212) and wild-type (WT) mice were subjected to either HFD or a normal diet (ND) for 28 weeks. Another group underwent abdominal aortic constriction (AAC) or a sham procedure and was monitored for 12 weeks. Inflammatory markers, histology, and echocardiography were used to assess the effects of these interventions. Results: TLR4\u2212\/\u2212 mice exhibited reduced cardiac hypertrophy and fibrosis after long-term HFD exposure compared to ND without affecting cardiac function. On the other hand, TLR4 deficiency worsened cardiac function in response to AAC, leading to decreased ejection fraction (EF%) and increased end-systolic volume (ESV). Conclusions: TLR4 deficiency provided protection against HFD-induced myocardial inflammation but impaired hemodynamic cardiac function under pressure overload conditions. These findings highlight the crucial role of TLR4 and its downstream signaling pathway in maintaining cardiac output during physiologic cardiac hypertrophy in response to pressure overload.<\/jats:p>","DOI":"10.3390\/nu15245139","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T11:28:07Z","timestamp":1702898887000},"page":"5139","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Toll-like Receptor 4 Differentially Modulates Cardiac Function in Response to Chronic Exposure to High-Fat Diet and Pressure Overload"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4544-9269","authenticated-orcid":false,"given":"Liping","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"},{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2816-5689","authenticated-orcid":false,"given":"Mohammad","family":"Jarrah","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hussein","family":"Herz","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Chu","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqun","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxiang","family":"Yuan","sequence":"additional","affiliation":[{"name":"The Collaborative Innovation Center, Jining Medical University, Jining 272067, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1402-580X","authenticated-orcid":false,"given":"Mohamad","family":"Mokadem","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA"},{"name":"Fraternal Order of Eagles Diabetes Research Center, The University of Iowa, Iowa City, IA 52242, USA"},{"name":"Obesity Research and Education Initiative, The University of Iowa, Iowa City, IA 52242, USA"},{"name":"Iowa City Veterans Affairs Health Care System, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,18]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Mortality in the United States, 2018","volume":"355","author":"Xu","year":"2020","journal-title":"NCHS Data Brief."},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1161\/CIR.0000000000000366","article-title":"Executive Summary: Heart Disease and Stroke Statistics\u20132016 Update: A Report from the American Heart Association","volume":"133","author":"Mozaffarian","year":"2016","journal-title":"Circulation"},{"key":"ref_4","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: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC","volume":"37","author":"Ponikowski","year":"2016","journal-title":"Eur. Heart. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"161","DOI":"10.21037\/atm.2017.03.107","article-title":"Morbidity and mortality associated with obesity","volume":"5","author":"Abdelaal","year":"2017","journal-title":"Ann. Transl. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1172\/JCI28898","article-title":"TLR4 links innate immunity and fatty acid\u2013induced insulin resistance","volume":"116","author":"Shi","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1210\/er.2014-1100","article-title":"TLR4 at the Crossroads of Nutrients, Gut Microbiota, and Metabolic Inflammation","volume":"36","author":"Velloso","year":"2015","journal-title":"Endocr. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.1016\/j.soard.2021.07.019","article-title":"Toll-like receptor 4 and myeloid differentiation factor 88 are required for gastric bypass-induced metabolic effects","volume":"17","author":"Ye","year":"2021","journal-title":"Surg. Obes. Relat. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9874109","DOI":"10.1155\/2018\/9874109","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_10","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.immuni.2010.03.012","article-title":"Intracellular Toll-like Receptors","volume":"32","author":"Blasius","year":"2010","journal-title":"Immunity"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/nri3446","article-title":"The history of Toll-like receptors\u2014Redefining innate immunity","volume":"13","author":"Golenbock","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/nri3735","article-title":"Pattern recognition receptors: Curbing gut inflammation","volume":"14","author":"Kugelberg","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.cell.2010.01.022","article-title":"Pattern Recognition Receptors and Inflammation","volume":"140","author":"Takeuchi","year":"2010","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.ijcard.2005.06.023","article-title":"Activated toll-like receptor 4 in monocytes is associated with heart failure after acute myocardial infarction","volume":"109","author":"Satoh","year":"2006","journal-title":"Int. J. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.1016\/j.bbadis.2017.01.010","article-title":"TLR4 knockout attenuated high fat diet-induced cardiac dysfunction via NF-\u03baB\/JNK-dependent activation of autophagy","volume":"1863","author":"Hu","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kessler, E.L., Wang, J.-W., Kok, B., Brans, M.A., Nederlof, A., van Stuijvenberg, L., Huang, C., Vink, A., Arslan, F., and Efimov, I.R. (2021). Ventricular TLR4 Levels Abrogate TLR2-Mediated Adverse Cardiac Remodeling upon Pressure Overload in Mice. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111823"},{"key":"ref_17","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. Hear. Fail."},{"key":"ref_18","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_19","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_20","doi-asserted-by":"crossref","first-page":"H1712","DOI":"10.1152\/ajpheart.00124.2004","article-title":"NF-kappaB activation is required for the development of cardiac hypertrophy in vivo","volume":"287","author":"Li","year":"2004","journal-title":"Am. J. Physiol. Heart. Circ. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.cardiores.2005.05.025","article-title":"Reduced cardiac hypertrophy in toll-like receptor 4-deficient mice following pressure overload","volume":"68","author":"Ha","year":"2005","journal-title":"Cardiovasc. Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Ma, Y., Zhang, X., Bao, H., Mi, S., Cai, W., Yan, H., and Hu, Z. (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_23","doi-asserted-by":"crossref","first-page":"e006908","DOI":"10.1161\/JAHA.117.006908","article-title":"Discovery of an Experimental Model of Unicuspid Aortic Valve","volume":"7","author":"Weiss","year":"2018","journal-title":"J. Am. Hear. Assoc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1161\/ATVBAHA.115.306912","article-title":"Fibrotic Aortic Valve Stenosis in Hypercholesterolemic\/Hypertensive Mice","volume":"36","author":"Chu","year":"2016","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.ijcard.2015.06.099","article-title":"ATF3-dependent cross-talk between cardiomyocytes and macrophages promotes cardiac maladaptive re-modeling","volume":"198","author":"Koren","year":"2015","journal-title":"Int. J. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jacc.2007.09.026","article-title":"Structural and functional remodeling of the left atrium: Clinical and therapeutic implications for atrial fibrillation","volume":"51","author":"Gersh","year":"2008","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"535241","DOI":"10.4061\/2011\/535241","article-title":"Cellular Interplay between Cardiomyocytes and Nonmyocytes in Cardiac Remodeling","volume":"2011","author":"Takeda","year":"2011","journal-title":"Int. J. Inflamm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"H850","DOI":"10.1152\/ajpheart.00419.2021","article-title":"Functional resilience of C57BL\/6J mouse heart to dietary fat overload","volume":"321","author":"Tadinada","year":"2021","journal-title":"Am. J. Physiol. Heart. Circ. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ehrentraut, H., Ehrentraut, S.F., 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_30","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_31","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1096\/fj.05-5133fje","article-title":"Absence of NF-kappaB subunit p50 improves heart failure after myocardial infarction","volume":"20","author":"Frantz","year":"2006","journal-title":"FASEB J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1002\/oby.21871","article-title":"Toll-like receptor 4 mediates fat, sugar, and umami taste preference and food intake and body weight regulation","volume":"25","author":"Camandola","year":"2017","journal-title":"Obesity"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1038\/oby.2008.210","article-title":"Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat","volume":"16","author":"Davis","year":"2008","journal-title":"Obesity"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3878","DOI":"10.1038\/ncomms4878","article-title":"Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance","volume":"5","author":"Jia","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1093\/abbs\/gmt092","article-title":"TLR4 is required for the obesity-induced pancreatic beta cell dysfunction","volume":"45","author":"Li","year":"2013","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Pierre, N., Deldicque, L., Barb\u00e9, C., Naslain, D., Cani, P.D., and Francaux, M. (2013). Toll-like receptor 4 knockout mice are protected against endoplasmic reticulum stress induced by a high-fat diet. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0065061"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1126\/science.1179721","article-title":"Metabolic syndrome and altered gut microbiota in mice lacking toll-like receptor 5","volume":"328","author":"Aitken","year":"2010","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6631","DOI":"10.1158\/0008-5472.CAN-15-3034","article-title":"Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and En-dotoxin Leakage","volume":"76","author":"Wang","year":"2016","journal-title":"Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"579036","DOI":"10.3389\/fcvm.2020.579036","article-title":"Key Player in Cardiac Hypertrophy, Emphasizing the Role of Toll-like Receptor 4","volume":"7","author":"Xiao","year":"2020","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1143583","DOI":"10.3389\/fcvm.2023.1143583","article-title":"Toll-like receptors in cardiac hypertrophy","volume":"10","author":"Zhang","year":"2023","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"E4079","DOI":"10.1073\/pnas.1315587110","article-title":"Intrinsic-mediated caspase activation is essential for cardiomyocyte hypertrophy","volume":"110","author":"Putinski","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/24\/5139\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:41:04Z","timestamp":1760132464000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/24\/5139"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,18]]},"references-count":41,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["nu15245139"],"URL":"https:\/\/doi.org\/10.3390\/nu15245139","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,18]]}}}