CD40L–CD40–TRAF signaling plays a role in atherosclerosis progression and affects the pathogenesis of coronary heart disease (CHD). We tested the hypothesis that CD40L–CD40–TRAF signaling is a potential therapeutic target in hyperlipidemia, diabetes, and hypertension. In mouse models of hyperlipidemia plus diabetes (db/db mice) or hypertension (1 mg/kg/d angiotensin-II for 7 days), TRAF6 inhibitor treatment (2.5 mg/kg/d for 7 or 14 days) normalized markers of oxidative stress and inflammation. As diabetes and hypertension are important comorbidities aggravating CHD, we explored whether the CD40L–CD40–TRAF signaling cascade and their associated inflammatory pathways are expressed in CHD patients suffering from comorbidities. Therefore, we analyzed vascular bypass material (aorta or internal mammary artery) and plasma from patients with CHD with diabetes and/or hypertension. Our Olink targeted plasma proteomic analysis using the IMMUNO-ONCOLOGY panel revealed a pattern of step-wise increase for 13/92 markers of low-grade inflammation with significant changes. CD40L or CD40 significantly correlated with 38 or 56 other inflammatory targets. In addition, specific gene clusters that correlate with the comorbidities were identified in isolated aortic mRNA of CHD patients through RNA-sequencing. These signaling clusters comprised CD40L–CD40–TRAF, immune system, hemostasis, muscle contraction, metabolism of lipids, developmental biology, and apoptosis. Finally, immunological analysis revealed key markers correlated with comorbidities in CHD patients, such as CD40L, NOX2, CD68, and 3-nitrotyrosine. These data indicate that comorbidities increase inflammatory pathways in CHD, and targeting these pathways will be beneficial in reducing cardiovascular events in CHD patients with comorbidities.

CD40L–CD40–TRAF 信号在动脉粥样硬化进展中发挥作用，并影响冠心病 (CHD) 的发病机制。我们测试了 CD40L-CD40-TRAF 信号传导是高脂血症、糖尿病和高血压的潜在治疗靶点的假设。在高脂血症加糖尿病（db/db 小鼠）或高血压（1 mg/kg/d 血管紧张素-II，持续 7 天）的小鼠模型中，TRAF6 抑制剂治疗（2.5 mg/kg/d，持续 7 或 14 天）使氧化标志物正常化压力和炎症。由于糖尿病和高血压是加重CHD的重要合并症，我们探讨了CD40L-CD40-TRAF信号级联及其相关的炎症通路是否在患有合并症的CHD患者中表达。因此，我们分析了患有糖尿病和/或高血压的冠心病患者的血管旁路材料（主动脉或乳内动脉）和血浆。我们使用免疫肿瘤学面板进行的 Olink 靶向血浆蛋白质组学分析揭示了 13/92 低度炎症标志物逐步增加的模式，并伴有显着变化。 CD40L 或 CD40 与 38 或 56 个其他炎症靶点显着相关。此外，通过 RNA 测序，在 CHD 患者分离的主动脉 mRNA 中鉴定出了与合并症相关的特定基因簇。这些信号簇包括 CD40L-CD40-TRAF、免疫系统、止血、肌肉收缩、脂质代谢、发育生物学和细胞凋亡。最后，免疫学分析揭示了与 CHD 患者合并症相关的关键标志物，例如 CD40L、NOX2、CD68 和 3-硝基酪氨酸。这些数据表明，合并症增加了冠心病的炎症通路，针对这些通路将有利于减少患有合并症的冠心病患者的心血管事件。