ITGBL1介导成纤维细胞-心肌细胞串扰促进心脏纤维化和肥大,Cardiovascular Research

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ITGBL1介导成纤维细胞-心肌细胞串扰促进心脏纤维化和肥大
Cardiovascular Research ( IF 10.2 ) Pub Date : 2023-06-30 , DOI: 10.1093/cvr/cvad104
XiaoQiang Chen ₁ , XinTao Li ₁ , XiaoYu Wu ₁ , Yu Ding ₁ , Ya Li ₁ , GenQing Zhou ₁ , Yong Wei ₁ , SongWen Chen ₁ , XiaoFeng Lu ₁ , Juan Xu ₁ , ShaoWen Liu ₁ , Jun Li ₁ , LiDong Cai ₁

Affiliation

成纤维细胞和心肌细胞之间的串扰在心力衰竭 (HF) 期间的心脏重塑中发挥着关键作用；然而，潜在的分子机制仍然不清楚。最近，一种分泌蛋白整合素β样1（ITGBL1）被发现对多种疾病有有害影响，如肿瘤、肺纤维化和肝纤维化；而 ITBBL1 对心力衰竭的影响尚不清楚。本研究的目的是评估其对容量超负荷引起的重塑的贡献。方法和结果在这项研究中，我们发现ITGBL1在多种心脏病中高表达，并在我们的TAC小鼠模型中得到验证，特别是在成纤维细胞中。为了研究ITGBL1在体外细胞实验中的作用，对新生大鼠成纤维细胞（NRCF）和心肌细胞（NRCM）进行进一步研究。我们发现，与 NRCM 相比，NRCF 表达高水平的 ITBBL1。同时，在血管紧张素-II (AngII) 或去氧肾上腺素 (PE) 刺激后，ITGBL1 在 NRCF 中上调，但在 NRCM 中没有上调。此外，ITGBL1过表达促进了NRCF的激活，而ITGBL1的敲低则减轻了AngII治疗下NRCF的激活。此外，NRCFs分泌的ITGBL1可以诱导NRCMs肥大。从机械角度来看，ITGBL1–NME1–TGF-β–Smad2/3 和 Wnt 信号通路被确定分别介导 NRCF 激活和 NRCM 肥大。最后，在 TAC 小鼠中敲低 ITBBL1 重现了体外研究结果，表明心脏纤维化、肥大减弱并改善了心脏功能。结论 ITBBL1 是成纤维细胞-心肌细胞串扰之间的重要功能介质，可能成为心力衰竭患者心脏重构的有效靶点。

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ITGBL1 mediates fibroblast–cardiomyocyte crosstalk to promote cardiac fibrosis and hypertrophy

Aims Crosstalk between fibroblasts and cardiomyocytes plays a critical role in cardiac remodeling during heart failure (HF); however, the underlying molecular mechanisms remain obscure. Recently, a secretory protein, Integrin beta-like 1 (ITGBL1) was revealed to have detrimental effects on several diseases, such as tumors, pulmonary fibrosis, and hepatic fibrosis; whereas the effect of ITGBL1 on heart failure is unclear. The purpose of this study was to evaluate its contribution to volume overload-induced remodeling. Methods and Results In this study, we identified ITGBL1 was highly expressed in varied heart diseases and validated in our TAC mice model, especially in fibroblasts. To investigate the role of ITGBL1 in in vitro cell experiments, neonatal rat fibroblasts (NRCFs) and cardiomyocytes (NRCMs) were performed for further study. We found that in comparison to NRCMs, NRCFs expressed high levels of ITGBL1. Meanwhile, ITGBL1 was upregulated in NRCFs, but not in NRCMs following angiotensin-II (AngII) or phenylephrine (PE) stimulation. Furthermore, ITGBL1 overexpression promoted NRCFs activation, whereas knockdown of ITGBL1 alleviated NRCFs activation under AngII treatment. Moreover, NRCFs-secreted ITGBL1 could induce NRCMs hypertrophy. Mechanically, ITGBL1–NME1–TGF-β–Smad2/3 and Wnt signaling pathways were identified to mediate NRCFs activation and NRCMs hypertrophy, respectively. Finally, knockdown of ITGBL1 in TAC mice recapitulated the in vitro findings, demonstrating blunted cardiac fibrosis, hypertrophy, and improved cardiac function. Conclusions ITGBL1 is an important functional mediator between fibroblast–cardiomyocyte crosstalk and could be an effective target for cardiac remodeling in HF patients.

更新日期：2023-06-30

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