{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T20:04:17Z","timestamp":1788552257332,"version":"build-2803163510"},"reference-count":57,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,1,1]],"date-time":"2021-01-01T00:00:00Z","timestamp":1609459200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81860080"],"award-info":[{"award-number":["81860080"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>As a pattern recognition receptor, Toll\u2010like receptor 7 (TLR7) widely presented in the endosomal membrane of various cells. However, the precise role and mechanism of TLR7 in septic cardiomyopathy remain unknown. This study aims to determine the role of TLR7 in cardiac dysfunction during sepsis and explore the mechanism of TLR7 in septic cardiomyopathy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We generated a mouse model of septic cardiomyopathy by challenging with lipopolysaccharide (LPS). TLR7\u2010knockout (TLR7<jats:sup>\u2212\/\u2212<\/jats:sup>), wild\u2010type (WT) mice, cardiac\u2010specific TLR7\u2010transgenic (cTG\u2010TLR7) overexpression, and littermates WT (LWT) mice were subjected to septic model. Additionally, to verify the role and mechanism of TLR7 in vitro, we transfected neonatal rat ventricular myocytes (NRVMs) with Ad\u2010TLR7 and TLR7 siRNA before LPS administration. The effects of TLR7 were assessed by Ca<jats:sup>2+<\/jats:sup> imaging, western blotting, immunostaining, and quantitative real\u2010time polymerase chain reaction (qPCR).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that TLR7 knockout markedly exacerbated sepsis\u2010induced systolic dysfunction. Moreover, cardiomyocytes isolated from TLR7<jats:sup>\u2212\/\u2212<\/jats:sup> mice displayed weaker Ca<jats:sup>2+<\/jats:sup> handling than that in WT mice in response to LPS. Conversely, TLR7 overexpression alleviated LPS\u2010induced systolic dysfunction, and loxoribine (TLR7\u2010specific agonist) improved LPS\u2010induced cardiac dysfunction. Mechanistically, these optimized effects were associated with enhanced the adenosine (cAMP)\u2010protein kinase A (PKA) pathway, which upregulated phosphorylate\u2010phospholamban (p\u2010PLN) (Ser16) and promoted sarco\/endoplasmic reticulum Ca<jats:sup>2+<\/jats:sup> ATPase (Serca) and Ryanodine Receptor 2 (RyR2) expression in the sarcoplasmic reticulum (SR), and ultimately restored Ca<jats:sup>2+<\/jats:sup> handling in response to sepsis. While improved Ca<jats:sup>2+<\/jats:sup> handling was abrogated after H89 (a specific PKA inhibitor) pretreatment in cardiomyocytes isolated from cTG\u2010TLR7 mice. Consistently, TLR7 overexpression improved LPS\u2010induced Ca<jats:sup>2+<\/jats:sup>\u2010handling decrement in NRVMs. Nevertheless, TLR7 knockdown showed a deteriorative phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data demonstrated that activation of TLR7 protected against sepsis\u2010induced cardiac dysfunction through promoting cAMP\u2010PKA\u2010PLN pathway, and we revealed that TLR7 might be a novel therapeutic target to block the septic cardiomyopathy and support systolic function during sepsis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.266","type":"journal-article","created":{"date-parts":[[2021,1,2]],"date-time":"2021-01-02T06:38:46Z","timestamp":1609569526000},"source":"Crossref","is-referenced-by-count":42,"title":["Activation of Toll\u2010like receptor 7 provides cardioprotection in septic cardiomyopathy\u2010induced systolic dysfunction"],"prefix":"10.1002","volume":"11","author":[{"given":"Xie","family":"Saiyang","sequence":"first","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan People's Republic of China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wu","family":"Qingqing","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan People's Republic of China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"man","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan People's Republic of China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan People's Republic of China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhang","family":"Min","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan People's Republic of China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Yun","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan People's Republic of China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi","family":"Wenke","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan People's Republic of China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wu","family":"Haiming","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan People's Republic of China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeng","family":"Xiaofeng","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan People's Republic of China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Si","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan People's Republic of China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo","family":"Haipeng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health Qilu Hospital of Shandong University  Jinan China"},{"name":"Department of Critical Care Medicine Qilu Hospital of Shandong University  Jinan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4883-4226","authenticated-orcid":false,"given":"Deng","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan People's Republic of China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan People's Republic of China"},{"name":"Department of Cardiology The Fifth Affiliated Hospital of Xinjiang Medical University  \u00dcr\u00fcmqi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2210-3169","authenticated-orcid":false,"given":"Tang","family":"Qizhu","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan People's Republic of China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,1]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.0287"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/2110-5820-1-6"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40560-015-0112-5"},{"key":"e_1_2_8_5_1","first-page":"5040","article-title":"Dexmedetomidine alleviates LPS\u2010induced septic cardiomyopathy via the cholinergic anti\u2010inflammatory pathway in mice","volume":"9","author":"Kong W","year":"2017","journal-title":"Am J Transl Res"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(02)09459-X"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02664"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0900196106"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20080162"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20071990"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e3181d99e67"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.01.022"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.07.018"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf3926"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1093616"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2015.06.012"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvz057"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvw231"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2012.145"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61889-4"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurjhf\/hfn002"},{"key":"e_1_2_8_22_1","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1172\/jci.insight.125618","article-title":"Iron\u2010deficiency anemia reduces cardiac contraction by downregulating RyR2 channels and suppressing SERCA pump activity","volume":"4","author":"Chung YJ","year":"2019","journal-title":"JCI Insight"},{"key":"e_1_2_8_23_1","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1093\/cvr\/cvz163","article-title":"Levosimendan prevents doxorubicin\u2010induced cardiotoxicity in time\u2010 and dose\u2010dependent manner: implications for inotropy","volume":"116","author":"Efentakis P","year":"2020","journal-title":"Cardiovasc Res"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1019755108"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1113\/EP087221"},{"key":"e_1_2_8_26_1","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1126\/scisignal.aaw1347","article-title":"TLR7 and TLR8 activate distinct pathways in monocytes during RNA virus infection","volume":"12","author":"De Marcken M","year":"2019","journal-title":"Sci Signal"},{"key":"e_1_2_8_27_1","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/s41418-019-0372-z","article-title":"FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin\u2010induced cardiotoxicity via activating AKT","volume":"27","author":"Zhang X","year":"2019","journal-title":"Cell Death Differ"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.028911"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000091871.54907.6B"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.11.1577"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000062469.83985.9B"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3036"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2014.04.005"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2006.02.069"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-003-1879-8"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/embr.201337945"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvp100"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2013.343"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature20583"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7119"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30696-2"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-018-2043-8"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)15326-3"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2014.06.003"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.CCM.0000256723.37586.A2"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.48"},{"key":"e_1_2_8_47_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41586-019-1612-6","article-title":"UNC93B1 recruits syntenin\u20101 to dampen TLR7 signalling and prevent autoimmunity","author":"Majer O","year":"2019","journal-title":"Nature"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0908971106"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2003.12.031"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0509324103"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10407"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi051226n"},{"key":"e_1_2_8_53_1","doi-asserted-by":"crossref","first-page":"26492","DOI":"10.1016\/S0021-9258(18)47221-3","article-title":"Identification of Ser38 as the site in cardiac sarcoplasmic reticulum Ca(2+)\u2010ATPase that is phosphorylated by Ca2+\/calmodulin\u2010dependent protein kinase","volume":"269","author":"Toyofuku T","year":"1994","journal-title":"J Biol Chem"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.70.4.670"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvy279"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.067306"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.313865"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.313916"}],"container-title":["Clinical and Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.266","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ctm2.266","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.266","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,3]],"date-time":"2023-09-03T06:41:00Z","timestamp":1693723260000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ctm2.266"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1]]},"references-count":57,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,1]]}},"alternative-id":["10.1002\/ctm2.266"],"URL":"https:\/\/doi.org\/10.1002\/ctm2.266","archive":["Portico"],"relation":{},"ISSN":["2001-1326","2001-1326"],"issn-type":[{"value":"2001-1326","type":"print"},{"value":"2001-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1]]},"article-number":"e266"}}