Department of Cardiology, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Clin Transl Med. 2023 Jun;13(6):e1296. doi: 10.1002/ctm2.1296.
The cardiac repair process following a myocardial infarction is a key factor in patient prognosis. In this repair process, cardiac fibrosis takes a critically important role. Among those featured genes for fibrosis, transforming growth factor beta (TGF-β) is known to be involved in the fibrosis in various organs. And bone morphogenetic protein (BMP)6 belongs to the TGF-β superfamily. Although BMPs are known to play exclusive roles in cardiac repair processes, the character of BMP6 in cardiac remodelling remains unclear.
This study aimed to investigate how BMP6 functioned in cardiac fibrosis following myocardial infarction (MI).
In this paper, we demonstrated that BMP6 expression was upregulated after myocardial infarction in wild-type (WT) mice. Furthermore, BMP6 mice showed a more significant decline in cardiac function and lower survival curves after MI. An enlarged infarct area, increased fibrosis and more pronounced inflammatory infiltration were observed in BMP6 mice compared to WT mice. The expression of collagen I, collagen III and α-SMA was increased in BMP6 mice. In vitro, through gain-of-function and loss-of-function experiments, it was demonstrated that BMP6 decreases collagen secretion in fibroblasts. Mechanistically, knocking down BMP6 promoted AP-1 phosphorylation, which in turn promotes CEMIP expression, led to an acceleration in the progression of cardiac fibrosis. Finally, it was found that rhBMP6 would alleviate ventricular remodelling abnormalities after myocardial infarction.
Therefore, BMP6 may be a novel molecular target for improving myocardial fibrosis and cardiac function after myocardial infarction.
心肌梗死后的心脏修复过程是患者预后的关键因素。在这个修复过程中，心脏纤维化起着至关重要的作用。在纤维化相关的基因中，转化生长因子-β（TGF-β）已知在各种器官的纤维化中发挥作用。骨形态发生蛋白 6（BMP6）属于 TGF-β超家族。尽管 BMPs 被认为在心脏修复过程中发挥独特的作用，但 BMP6 在心脏重构中的特性尚不清楚。
本研究旨在探讨 BMP6 在心肌梗死后心脏纤维化中的作用。
本文表明，BMP6 在野生型（WT）小鼠心肌梗死后表达上调。此外，BMP6 小鼠在心肌梗死后心脏功能下降更明显，存活率更低。与 WT 小鼠相比，BMP6 小鼠的梗死面积增大，纤维化增加，炎症浸润更明显。BMP6 小鼠的胶原 I、胶原 III 和 α-SMA 表达增加。在体外，通过功能获得和功能丧失实验表明，BMP6 可减少成纤维细胞胶原分泌。机制上，敲低 BMP6 促进了 AP-1 磷酸化，进而促进 CEMIP 的表达，加速了心脏纤维化的进展。最后，发现 rhBMP6 可减轻心肌梗死后心室重构异常。
因此，BMP6 可能是改善心肌梗死后心肌纤维化和心功能的新的分子靶点。
