Wu Anbiao, Zhang Lihong, Chen Jingyang, Li Hekai, Yang Pingzhen, Chen Minsheng, Liu Qicai
Guangdong Provincial Biomedical Engineering Technology Research, Center for Cardiovascular Disease; Sino-Japanese Cooperation Platform for Translational Research in Heart Failure; Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People's Republic of China.
Nanfang Hospital, the First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, People's Republic of China.
Mol Cell Biochem. 2021 Jul;476(7):2685-2701. doi: 10.1007/s11010-021-04111-7. Epub 2021 Mar 5.
Cardiac fibrosis is an important pathological change after myocardial infarction (MI). Its progression is essential for post-MI infarct healing, during which transforming growth factor beta1 (TGF-β1) plays a critical role. Limb-bud and Heart (LBH), a newly discovered target gene of TGF-β1, was shown to promote normal cardiogenesis. αB-crystallin (CRYAB), an LBH-interacting protein, was demonstrated to be involved in TGF-β1-induced fibrosis. The roles and molecular mechanisms of LBH and CRYAB during cardiac fibrosis remain largely unexplored. In this study, we investigated the alterations of LBH and CRYAB expression in mouse cardiac tissue after MI. LBH and CRYAB were upregulated in activated cardiac fibroblasts (CFs), while in vitro TGF-β1 stimulation induced the upregulation of LBH, CRYAB, and fibrogenic genes in primary CFs of neonatal rats. The results of the ectopic expression of LBH proved that LBH accelerated CF proliferation under hypoxia, mediated the expression of CRYAB and fibrogenic genes, and promoted epithelial-mesenchymal transition (EMT)-like processes in rat CFs, while subsequent CRYAB silencing reversed the effects induced by elevated LBH expression. We also verified the protein-protein interaction (PPI) between LBH and CRYAB in fibroblasts. In summary, our work demonstrated that LBH promotes the proliferation of CFs, mediates TGF-β1-induced fibroblast-to-myofibroblast transition and EMT-like processes through CRYAB upregulation, jointly functioning in post-MI infarct healing. These findings suggest that LBH could be a promising potential target for the study of cardiac repair and cardiac fibrosis.
心脏纤维化是心肌梗死（MI）后的一种重要病理变化。其进展对于MI后梗死愈合至关重要，在此过程中转化生长因子β1（TGF-β1）发挥着关键作用。肢芽与心脏（LBH）是新发现的TGF-β1靶基因，已证明其可促进正常心脏发生。αB-晶状体蛋白（CRYAB）是一种与LBH相互作用的蛋白，已证明其参与TGF-β1诱导的纤维化过程。LBH和CRYAB在心脏纤维化过程中的作用及分子机制在很大程度上仍未被探索。在本研究中，我们调查了MI后小鼠心脏组织中LBH和CRYAB表达的变化。LBH和CRYAB在活化的心脏成纤维细胞（CFs）中上调，而体外TGF-β1刺激可诱导新生大鼠原代CFs中LBH、CRYAB和纤维化基因的上调。LBH异位表达的结果证明，LBH在缺氧条件下加速CF增殖，介导CRYAB和纤维化基因的表达，并促进大鼠CFs中的上皮-间质转化（EMT）样过程，而随后的CRYAB沉默可逆转LBH表达升高所诱导的效应。我们还验证了成纤维细胞中LBH与CRYAB之间的蛋白质-蛋白质相互作用（PPI）。总之，我们的工作表明，LBH通过上调CRYAB促进CFs增殖，介导TGF-β1诱导的成纤维细胞向肌成纤维细胞转化和EMT样过程，共同参与MI后梗死愈合。这些发现表明，LBH可能是心脏修复和心脏纤维化研究中一个有前景的潜在靶点。
