Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, 200233, Shanghai, China.
J Cardiovasc Transl Res. 2023 Jun;16(3):608-623. doi: 10.1007/s12265-022-10328-8. Epub 2022 Nov 8.
Timely formation of collagen-rich-scar is of importance to prevent ventricular rupture after myocardial infarction (MI). Chil1 (Chitinase 3-like 1) is a secreted protein associated with tissue remodeling response. However, its function in MI progression remains elusive. Chil1 was downregulated in the injured area overall post-MI. Overexpression of Chil1 markedly reduced cardiac rupture, increased wall thickness, and improved cardiac function post-MI due to collagen-rich-scar formation and extracellular matrix remodeling. In vitro, Chil1 induced the transformation of fibroblasts to myofibroblasts. Mechanistically, a phosphoproteomics study revealed that Chil1 binded to the EGFR enhancing RAF/MEK1/ERK signaling pathway to exert cardiac protection function. The effects of Chil1 on fibroblasts transformation and cardiac protections after MI were partially abolished by co-treated with RAF inhibitor. Together, our findings identify Chil1 as a protection factor in MI progression through binding to EGFR which further activates RAF/MEK1/ERK signaling pathway.
胶原丰富的瘢痕的及时形成对于预防心肌梗死后心室破裂至关重要。Chil1（几丁质酶 3 样 1）是一种与组织重塑反应相关的分泌蛋白。然而，其在心肌梗死进展中的作用仍不清楚。心肌梗死后，Chil1 在损伤区域总体下调。Chil1 的过表达显著减少了心肌梗死后的心脏破裂、增加了壁厚度并改善了心脏功能，这是由于胶原丰富的瘢痕形成和细胞外基质重塑。在体外，Chil1 诱导成纤维细胞向肌成纤维细胞转化。从机制上讲，磷酸蛋白质组学研究表明，Chil1 与 EGFR 结合，增强 RAF/MEK1/ERK 信号通路，发挥心脏保护作用。用 RAF 抑制剂共同处理部分消除了 Chil1 对心肌梗死后成纤维细胞转化和心脏保护的作用。总之，我们的研究结果表明，Chil1 通过与 EGFR 结合，进一步激活 RAF/MEK1/ERK 信号通路，成为心肌梗死进展中的保护因子。
