A combinatorial attack strategy uncovers a molecular rationale for treating inflammatory cardiomyopathy

Here we show how the cardiac transcriptome evolves during murine myocarditis revealing early and persistent activation of cytokine and chemokine-signalling pathways together with innate immune, antigen-presentation, complement and cell-adhesion pathway activation. We identified a 50-gene subnetwork based on expression importance and quantified network tolerance to combinatorial node removal to determine target-specific therapeutic potential. Combinatorial attack of Traf2, Nfkb1, Rac1 and Vav1 causes 80% subnetwork disconnection. NFKB1 and RAC1 are targeted by prednisolone and azathioprine, creating 56% network disconnection, establishing a molecular rationale for immunosuppressive therapy. Additional combinatorial attack of BTK and PIK3CD with approved therapeutics causes 72% network disconnection, suggesting that they could be re-purposed to treat inflammatory cardiomyopathy. We propose that the combinatorial attack strategy developed here could be applied to other immune-mediated diseases. Analyzing evolution of cardiac transcriptome during development of autoimmune myocarditis

本研究阐明了小鼠心肌炎（murine myocarditis）进程中心脏转录组（cardiac transcriptome）的动态演变规律，揭示了细胞因子与趋化因子信号通路，以及先天免疫、抗原呈递、补体及细胞黏附通路的早期持续激活。本研究基于基因表达重要性筛选得到一个包含50个基因的子网（subnetwork），并通过量化网络对组合节点移除的耐受能力，评估了各靶点的特异性治疗潜力。同时靶向Traf2、Nfkb1、Rac1与Vav1的组合干预可使该子网的连通性丧失80%。泼尼松龙（prednisolone）与硫唑嘌呤（azathioprine）可靶向NFKB1和RAC1，使网络连通性降低56%，为免疫抑制治疗提供了分子理论依据。使用已获批药物额外靶向BTK与PIK3CD开展组合干预，可使网络连通性降低72%，提示二者可被重新定位用于治疗炎症性心肌病（inflammatory cardiomyopathy）。本研究提出，本次开发的组合干预策略可推广应用于其他免疫介导性疾病的研究。本研究同时针对自身免疫性心肌炎（autoimmune myocarditis）发生过程中的心脏转录组演变展开了分析。