National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.
Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, 8 College Road, Singapore, 169857, Singapore.
J Cardiovasc Transl Res. 2021 Apr;14(2):222-228. doi: 10.1007/s12265-020-10054-z. Epub 2020 Jun 26.
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. Figa Graphical Abstract.
目前尚无针对心脏纤维化的特定治疗方法。我们在两种临床前模型中测试了中和抗 IL11 抗体 (X203) 减少心脏纤维化的功效：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 C57BL/6J 小鼠接受 TAC 治疗 2 周。在第二个模型中，通过皮下泵连续 4 周给予小鼠血管紧张素 II。在这两种模型中，小鼠在手术后 24 小时开始每周两次接受 20mg/kg 的 X203 或同种型对照抗体。通过 RT-qPCR、Western blot、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。在这两种模型中，X203 均显著降低了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）。IL11 的药理学靶向治疗可减少临床前模型中的心脏纤维化。Figa 图形摘要。
