Feng Renlei, Liu Hongli, Chen Yunqing
Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
Department of Geriatrics, Chongqing General Hospital, Chongqing University, Chongqing, 401147, China.
BMC Cardiovasc Disord. 2025 Jan 31;25(1):65. doi: 10.1186/s12872-025-04517-x.
JAK/STAT pathway is closely involved in the organ fibrotic process. The current study aimed to investigate the impact of baricitinib, an oral selective JAK1/JAK2 inhibitor, on the myocardial fibrosis in vivo and the activation of cardiac fibroblasts in vitro.
The mouse myocardial fibrosis model was established by isoproterenol (ISO) treatment, then was treated by baricitinib. The activation of mouse cardiac fibroblasts was established by TGF-β1 stimulation, then was treated by baricitinib with several concentrations. Besides, JAK2 was knocked down by small interfering RNA (siRNA) in TGF-β1-stimulated mouse cardiac fibroblasts.
Baricitinib not only attenuated myocardial cell widening, inflammatory infiltration, fibrous tissue, and heart index, but also reduced collagen volume fraction, the expressions of Col1, Col3, α-SMA, Fn, MMP9, and TIMP1 in ISO-induced myocardial fibrosis mice. Meanwhile, baricitinib decreased the expressions of p-STAT3 and TGF-βRII in these mice. Interestingly, in TGF-β1-stimulated cardiac fibroblasts, baricitinib decreased the expressions of Col1, Col3, α-SMA, Fn, MMP9, and TIMP1 in a dose-dependent manner (From 10 to 2000 nM), also exhibited a dose-dependent impact on the expressions of p-STAT3 and TGF-βRII. Finally, JAK2 knockdown by siRNA downregulated the expressions of Col1, Col3, α-SMA, and Fn in TGF-β1-stimulated cardiac fibroblasts.
Inhibition of JAK/STAT pathway by baricitinib represses the myocardial fibrosis in vivo and in vitro, indicating baricitinib may be a treatment option for myocardial fibrosis, while further validation is needed.
JAK/STAT信号通路与器官纤维化过程密切相关。本研究旨在探讨口服选择性JAK1/JAK2抑制剂巴瑞替尼对体内心肌纤维化及体外心脏成纤维细胞活化的影响。
通过异丙肾上腺素（ISO）处理建立小鼠心肌纤维化模型，然后用巴瑞替尼进行治疗。通过转化生长因子-β1（TGF-β1）刺激建立小鼠心脏成纤维细胞活化模型，然后用不同浓度的巴瑞替尼进行处理。此外，在TGF-β1刺激的小鼠心脏成纤维细胞中，用小干扰RNA（siRNA）敲低JAK2。
巴瑞替尼不仅减轻了心肌细胞增宽、炎症浸润、纤维组织和心脏指数，还降低了ISO诱导的心肌纤维化小鼠的胶原容积分数、Col1、Col3、α-SMA、Fn、MMP9和TIMP1的表达。同时，巴瑞替尼降低了这些小鼠中p-STAT3和TGF-βRII的表达。有趣的是，在TGF-β1刺激的心脏成纤维细胞中，巴瑞替尼以剂量依赖性方式（从10到2000 nM）降低了Col1、Col3、α-SMA、Fn、MMP9和TIMP1的表达，对p-STAT3和TGF-βRII的表达也表现出剂量依赖性影响。最后，用siRNA敲低JAK2可下调TGF-β1刺激的心脏成纤维细胞中Col1、Col3、α-SMA和Fn的表达。
巴瑞替尼抑制JAK/STAT信号通路可在体内和体外抑制心肌纤维化，表明巴瑞替尼可能是心肌纤维化的一种治疗选择，但仍需进一步验证。
