Therapeutic Targeting of Interleukin-11 Signalling Reduces Pressure Overload-Induced Cardiac Fibrosis in Mice
Therapeutic Targeting of Interleukin-11 Signalling Reduces Pressure Overload-Induced Cardiac Fibrosis in Mice
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DOI：
10.1007/s12265-020-10054-z
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发表时间：
2020-06-26
影响因子：
3.4
通讯作者：
Cook, Stuart A.
中科院分区：
文献类型：
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作者：
Corden, Ben;Lim, Wei-Wen;Cook, Stuart A.
目前没有针对心脏纤维化的特异性治疗方法。我们在两种临床前模型中测试了中和抗IL 11抗体（X203）减少心脏纤维化的功效：横主动脉缩窄（TAC）和慢性血管紧张素II输注（AngII）。在第一个模型中，雄性C57 BL/6 J小鼠接受TAC 2周。在第二个模型中，小鼠通过皮下泵连续接受血管紧张素II 4周。在两种模型中，小鼠从术后24小时开始每周两次接受20 mg/kg X203或同种型对照抗体。通过RT-qPCR、Western印迹、组织学和胶原（羟脯氨酸）测定评估心脏纤维化和细胞外基质基因表达。在两种模型中，X203显著降低促纤维化基因表达和心肌纤维化（TAC：总胶原减少51%，P <0.001，血管周围纤维化减少39%，P < 0.001; AngII：总胶原减少17%，P = 0.04，血管周围纤维化减少83%，P < 0.001）。IL 11的药理学靶向作用减少了临床前模型中的心脏纤维化。
There are currently no specific treatments for cardiac fibrosis. We tested the efficacy of a neutralising anti-IL11 antibody (X203) to reduce cardiac fibrosis in two preclinical models: transverse aortic constriction (TAC) and chronic angiotensin II infusion (AngII). In the first model, male C57BL/6J mice were subjected to TAC for 2 weeks. In the second model, mice received continuous angiotensin II for 4 weeks via subcutaneous pump. In both models, mice received either 20 mg/kg of X203 or isotype-control antibody twice-weekly, starting 24 h after surgery. Cardiac fibrosis and extracellular matrix gene expression were assessed by RT-qPCR, Western blot, histology and collagen (hydroxyproline) assays. In both models, X203 significantly reduced pro-fibrotic gene expression and myocardial fibrosis (TAC: 51% reduction in total collagen,P < 0.001, 39% in perivascular fibrosis,P < 0.001; AngII: 17% reduction in total collagen,P = 0.04, 83% in perivascular fibrosis,P < 0.001). Pharmacological targeting of IL11 reduces cardiac fibrosis in preclinical models.