LCZ696 Attenuated Doxorubicin-Induced Chronic Cardiomyopathy Through the TLR2-MyD88 Complex Formation
Background and PurposeThe profibrotic and proinflammatory effects induced by doxorubicin (DOX) are key processes in the development of serious heart damage. Lack of effective drugs and the unclear mechanisms of its side effects limit the clinical treatment of DOX-induced cardiac injury. This study a...
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Frontiers Media S.A.
2021-04-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.654051/full |
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| author | Shiju Ye Shiju Ye Shiju Ye Lan Su Lan Su Peiren Shan Peiren Shan Bozhi Ye Bozhi Ye Shengjie Wu Shengjie Wu Guang Liang Guang Liang Weijian Huang Weijian Huang |
| author_facet | Shiju Ye Shiju Ye Shiju Ye Lan Su Lan Su Peiren Shan Peiren Shan Bozhi Ye Bozhi Ye Shengjie Wu Shengjie Wu Guang Liang Guang Liang Weijian Huang Weijian Huang |
| author_sort | Shiju Ye |
| collection | DOAJ |
| description | Background and PurposeThe profibrotic and proinflammatory effects induced by doxorubicin (DOX) are key processes in the development of serious heart damage. Lack of effective drugs and the unclear mechanisms of its side effects limit the clinical treatment of DOX-induced cardiac injury. This study aimed to explore the protective role of LCZ696 and the potential mechanism of Toll-like receptor 2 (TLR2) in doxorubicin-induced cardiac failure.Experimental ApproachDOX (5 mg/kg/week, three times) was used to establish a chronic cardiomyopathy mouse model. Heart function tests, pathology examinations and molecular biology analyses were used to explore the effects of LCZ696 and TLR2 deficiency in vivo and in vitro. Computational docking was applied to predict the key residues for protein-ligand interaction.Key ResultsThe EF% declined, and the LVIDd, pro-fibrosis marker levels and NF-κB related inflammatory response increased in the chronic cardiomyopathy group induced by DOX. LCZ696 treatment and TLR2 deficiency reversed these heart damage in vivo. In H9C2 cells, pre-treatment with LCZ696 and TLR2 knockdown suppressed the DOX-induced high expression of profibrotic and proinflammatory markers. Moreover, DOX notably increased the TLR2-MyD88 interaction in vivo and in vitro, which was inhibited by LCZ696. Finally, we demonstrated the direct interaction between DOX and TLR2 via hydrogen bonds on Pro-681 and Glu-727 and Pro-681 and Ser-704 may be the key residues by which LCZ696 affects the interaction between DOX and TLR2.Conclusion and ImplicationsLCZ696 prevents DOX-induced cardiac dilation failure, fibrosis and inflammation by reducing the formation of TLR2-MyD88 complexes. LZC696 may be a potential effective drug to treat DOX-induced heart failure. |
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| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-14T11:57:16Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-564d9214e7894052b5823bef90b2ac592022-12-21T23:02:05ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-04-01910.3389/fcell.2021.654051654051LCZ696 Attenuated Doxorubicin-Induced Chronic Cardiomyopathy Through the TLR2-MyD88 Complex FormationShiju Ye0Shiju Ye1Shiju Ye2Lan Su3Lan Su4Peiren Shan5Peiren Shan6Bozhi Ye7Bozhi Ye8Shengjie Wu9Shengjie Wu10Guang Liang11Guang Liang12Weijian Huang13Weijian Huang14Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaThe Key Laboratory of Cardiovascular Disease of Wenzhou, Wenzhou, ChinaChemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, ChinaDepartment of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaThe Key Laboratory of Cardiovascular Disease of Wenzhou, Wenzhou, ChinaDepartment of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaThe Key Laboratory of Cardiovascular Disease of Wenzhou, Wenzhou, ChinaDepartment of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaThe Key Laboratory of Cardiovascular Disease of Wenzhou, Wenzhou, ChinaDepartment of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaThe Key Laboratory of Cardiovascular Disease of Wenzhou, Wenzhou, ChinaDepartment of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaChemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, ChinaDepartment of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaThe Key Laboratory of Cardiovascular Disease of Wenzhou, Wenzhou, ChinaBackground and PurposeThe profibrotic and proinflammatory effects induced by doxorubicin (DOX) are key processes in the development of serious heart damage. Lack of effective drugs and the unclear mechanisms of its side effects limit the clinical treatment of DOX-induced cardiac injury. This study aimed to explore the protective role of LCZ696 and the potential mechanism of Toll-like receptor 2 (TLR2) in doxorubicin-induced cardiac failure.Experimental ApproachDOX (5 mg/kg/week, three times) was used to establish a chronic cardiomyopathy mouse model. Heart function tests, pathology examinations and molecular biology analyses were used to explore the effects of LCZ696 and TLR2 deficiency in vivo and in vitro. Computational docking was applied to predict the key residues for protein-ligand interaction.Key ResultsThe EF% declined, and the LVIDd, pro-fibrosis marker levels and NF-κB related inflammatory response increased in the chronic cardiomyopathy group induced by DOX. LCZ696 treatment and TLR2 deficiency reversed these heart damage in vivo. In H9C2 cells, pre-treatment with LCZ696 and TLR2 knockdown suppressed the DOX-induced high expression of profibrotic and proinflammatory markers. Moreover, DOX notably increased the TLR2-MyD88 interaction in vivo and in vitro, which was inhibited by LCZ696. Finally, we demonstrated the direct interaction between DOX and TLR2 via hydrogen bonds on Pro-681 and Glu-727 and Pro-681 and Ser-704 may be the key residues by which LCZ696 affects the interaction between DOX and TLR2.Conclusion and ImplicationsLCZ696 prevents DOX-induced cardiac dilation failure, fibrosis and inflammation by reducing the formation of TLR2-MyD88 complexes. LZC696 may be a potential effective drug to treat DOX-induced heart failure.https://www.frontiersin.org/articles/10.3389/fcell.2021.654051/fulldoxorubicinLZC696toll-like receptorsheart failuremolecular target |
| spellingShingle | Shiju Ye Shiju Ye Shiju Ye Lan Su Lan Su Peiren Shan Peiren Shan Bozhi Ye Bozhi Ye Shengjie Wu Shengjie Wu Guang Liang Guang Liang Weijian Huang Weijian Huang LCZ696 Attenuated Doxorubicin-Induced Chronic Cardiomyopathy Through the TLR2-MyD88 Complex Formation Frontiers in Cell and Developmental Biology doxorubicin LZC696 toll-like receptors heart failure molecular target |
| title | LCZ696 Attenuated Doxorubicin-Induced Chronic Cardiomyopathy Through the TLR2-MyD88 Complex Formation |
| title_full | LCZ696 Attenuated Doxorubicin-Induced Chronic Cardiomyopathy Through the TLR2-MyD88 Complex Formation |
| title_fullStr | LCZ696 Attenuated Doxorubicin-Induced Chronic Cardiomyopathy Through the TLR2-MyD88 Complex Formation |
| title_full_unstemmed | LCZ696 Attenuated Doxorubicin-Induced Chronic Cardiomyopathy Through the TLR2-MyD88 Complex Formation |
| title_short | LCZ696 Attenuated Doxorubicin-Induced Chronic Cardiomyopathy Through the TLR2-MyD88 Complex Formation |
| title_sort | lcz696 attenuated doxorubicin induced chronic cardiomyopathy through the tlr2 myd88 complex formation |
| topic | doxorubicin LZC696 toll-like receptors heart failure molecular target |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.654051/full |
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