Prevention of neointimal hyperplasia after coronary artery bypass graft via local delivery of sirolimus and rosuvastatin: network pharmacology and in vivo validation
Abstract Background Coronary artery bypass graft (CABG) is generally used to treat complex coronary artery disease. Treatment success is affected by neointimal hyperplasia (NIH) of graft and anastomotic sites. Although sirolimus and rosuvastatin individually inhibit NIH progression, the efficacy of...
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-024-04875-8 |
| _version_ | 1797273472499449856 |
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| author | Ji-yeon Ryu Eui Hwa Jang JiYong Lee Jung-Hwan Kim Young-Nam Youn |
| author_facet | Ji-yeon Ryu Eui Hwa Jang JiYong Lee Jung-Hwan Kim Young-Nam Youn |
| author_sort | Ji-yeon Ryu |
| collection | DOAJ |
| description | Abstract Background Coronary artery bypass graft (CABG) is generally used to treat complex coronary artery disease. Treatment success is affected by neointimal hyperplasia (NIH) of graft and anastomotic sites. Although sirolimus and rosuvastatin individually inhibit NIH progression, the efficacy of combination treatment remains unknown. Methods We identified cross-targets associated with CABG, sirolimus, and rosuvastatin by using databases including DisGeNET and GeneCards. GO and KEGG pathway enrichment analyses were conducted using R studio, and target proteins were mapped in PPI networks using Metascape and Cytoscape. For in vivo validation, we established a balloon-injured rabbit model by inducing NIH and applied a localized perivascular drug delivery device containing sirolimus and rosuvastatin. The outcomes were evaluated at 1, 2, and 4 weeks post-surgery. Results We identified 115 shared targets between sirolimus and CABG among databases, 23 between rosuvastatin and CABG, and 96 among all three. TNF, AKT1, and MMP9 were identified as shared targets. Network pharmacology predicted the stages of NIH progression and the corresponding signaling pathways linked to sirolimus (acute stage, IL6/STAT3 signaling) and rosuvastatin (chronic stage, Akt/MMP9 signaling). In vivo experiments demonstrated that the combination of sirolimus and rosuvastatin significantly suppressed NIH progression. This combination treatment also markedly decreased the expression of inflammation and Akt signaling pathway-related proteins, which was consistent with the predictions from network pharmacology analysis. Conclusions Sirolimus and rosuvastatin inhibited pro-inflammatory cytokine production during the acute stage and regulated Akt/mTOR/NF-κB/STAT3 signaling in the chronic stage of NIH progression. These potential synergistic mechanisms may optimize treatment strategies to improve long-term patency after CABG. Graphical Abstract |
| first_indexed | 2024-03-07T14:43:46Z |
| format | Article |
| id | doaj.art-8556b3b8e1ec4fc0b3858c2b56329d73 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-07T14:43:46Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-8556b3b8e1ec4fc0b3858c2b56329d732024-03-05T20:06:38ZengBMCJournal of Translational Medicine1479-58762024-02-0122111810.1186/s12967-024-04875-8Prevention of neointimal hyperplasia after coronary artery bypass graft via local delivery of sirolimus and rosuvastatin: network pharmacology and in vivo validationJi-yeon Ryu0Eui Hwa Jang1JiYong Lee2Jung-Hwan Kim3Young-Nam Youn4Division of Cardiovascular Surgery, Department of Thoracic and Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei University College of MedicineDivision of Cardiovascular Surgery, Department of Thoracic and Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei University College of MedicineSchool of Mechanical Engineering, Yonsei UniversityDivision of Cardiovascular Surgery, Department of Thoracic and Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei University College of MedicineDivision of Cardiovascular Surgery, Department of Thoracic and Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei University College of MedicineAbstract Background Coronary artery bypass graft (CABG) is generally used to treat complex coronary artery disease. Treatment success is affected by neointimal hyperplasia (NIH) of graft and anastomotic sites. Although sirolimus and rosuvastatin individually inhibit NIH progression, the efficacy of combination treatment remains unknown. Methods We identified cross-targets associated with CABG, sirolimus, and rosuvastatin by using databases including DisGeNET and GeneCards. GO and KEGG pathway enrichment analyses were conducted using R studio, and target proteins were mapped in PPI networks using Metascape and Cytoscape. For in vivo validation, we established a balloon-injured rabbit model by inducing NIH and applied a localized perivascular drug delivery device containing sirolimus and rosuvastatin. The outcomes were evaluated at 1, 2, and 4 weeks post-surgery. Results We identified 115 shared targets between sirolimus and CABG among databases, 23 between rosuvastatin and CABG, and 96 among all three. TNF, AKT1, and MMP9 were identified as shared targets. Network pharmacology predicted the stages of NIH progression and the corresponding signaling pathways linked to sirolimus (acute stage, IL6/STAT3 signaling) and rosuvastatin (chronic stage, Akt/MMP9 signaling). In vivo experiments demonstrated that the combination of sirolimus and rosuvastatin significantly suppressed NIH progression. This combination treatment also markedly decreased the expression of inflammation and Akt signaling pathway-related proteins, which was consistent with the predictions from network pharmacology analysis. Conclusions Sirolimus and rosuvastatin inhibited pro-inflammatory cytokine production during the acute stage and regulated Akt/mTOR/NF-κB/STAT3 signaling in the chronic stage of NIH progression. These potential synergistic mechanisms may optimize treatment strategies to improve long-term patency after CABG. Graphical Abstracthttps://doi.org/10.1186/s12967-024-04875-8SirolimusRosuvastatinIntimal hyperplasiaInflammationNetwork pharmacology |
| spellingShingle | Ji-yeon Ryu Eui Hwa Jang JiYong Lee Jung-Hwan Kim Young-Nam Youn Prevention of neointimal hyperplasia after coronary artery bypass graft via local delivery of sirolimus and rosuvastatin: network pharmacology and in vivo validation Journal of Translational Medicine Sirolimus Rosuvastatin Intimal hyperplasia Inflammation Network pharmacology |
| title | Prevention of neointimal hyperplasia after coronary artery bypass graft via local delivery of sirolimus and rosuvastatin: network pharmacology and in vivo validation |
| title_full | Prevention of neointimal hyperplasia after coronary artery bypass graft via local delivery of sirolimus and rosuvastatin: network pharmacology and in vivo validation |
| title_fullStr | Prevention of neointimal hyperplasia after coronary artery bypass graft via local delivery of sirolimus and rosuvastatin: network pharmacology and in vivo validation |
| title_full_unstemmed | Prevention of neointimal hyperplasia after coronary artery bypass graft via local delivery of sirolimus and rosuvastatin: network pharmacology and in vivo validation |
| title_short | Prevention of neointimal hyperplasia after coronary artery bypass graft via local delivery of sirolimus and rosuvastatin: network pharmacology and in vivo validation |
| title_sort | prevention of neointimal hyperplasia after coronary artery bypass graft via local delivery of sirolimus and rosuvastatin network pharmacology and in vivo validation |
| topic | Sirolimus Rosuvastatin Intimal hyperplasia Inflammation Network pharmacology |
| url | https://doi.org/10.1186/s12967-024-04875-8 |
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