Division of Cardiovascular Surgery, Department of Thoracic and Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, 03722, South Korea.
School of Mechanical Engineering, Yonsei University, Seoul, 03722, South Korea.
J Transl Med. 2024 Feb 16;22(1):166. doi: 10.1186/s12967-024-04875-8.
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.
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.
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.
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.
冠状动脉旁路移植术（CABG）通常用于治疗复杂的冠状动脉疾病。移植物和吻合部位的新生内膜增生（NIH）会影响治疗效果。虽然西罗莫司和瑞舒伐他汀单独抑制 NIH 进展，但联合治疗的疗效尚不清楚。
我们通过使用 DisGeNET 和 GeneCards 等数据库来识别与 CABG、西罗莫司和瑞舒伐他汀相关的交叉靶点。使用 R 工作室进行 GO 和 KEGG 通路富集分析，并使用 Metascape 和 Cytoscape 将靶蛋白映射到 PPI 网络中。为了进行体内验证，我们通过诱导 NIH 建立了球囊损伤的兔模型，并应用了含有西罗莫司和瑞舒伐他汀的局部血管周围药物输送装置。术后 1、2 和 4 周评估结果。
我们在数据库中鉴定出 115 个西罗莫司和 CABG 之间的共享靶点，23 个瑞舒伐他汀和 CABG 之间的共享靶点，96 个所有三个之间的共享靶点。TNF、AKT1 和 MMP9 被鉴定为共享靶点。网络药理学预测了 NIH 进展的阶段和与西罗莫司（急性阶段，IL6/STAT3 信号）和瑞舒伐他汀（慢性阶段，Akt/MMP9 信号）相关的相应信号通路。体内实验表明，西罗莫司和瑞舒伐他汀联合显著抑制 NIH 进展。这种联合治疗还显著降低了炎症和 Akt 信号通路相关蛋白的表达，这与网络药理学分析的预测结果一致。
西罗莫司和瑞舒伐他汀在 NIH 进展的急性期抑制促炎细胞因子的产生，并在慢性期调节 Akt/mTOR/NF-κB/STAT3 信号通路。这些潜在的协同机制可能优化治疗策略，以提高 CABG 后的长期通畅率。
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