Department of Cardiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing, China.
Cell Commun Signal. 2024 Sep 20;22(1):444. doi: 10.1186/s12964-024-01826-0.
Cardiac maladaptive remodeling is one of the leading causes of heart failure with highly complicated pathogeneses. The E3 ligase tripartite motif containing 35 (TRIM35) has been identified as a crucial regulator governing cellular growth, immune responses, and metabolism. Nonetheless, the role of TRIM35 in fibroblasts in cardiac remodeling remains elusive.
Heart tissues from human donors were used to verify tissue-specific expression of TRIM35. Fibroblast-specific Trim35 gene knockout mice (Trim35) were used to investigate the function of TRIM35 in fibroblasts. Cardiac function, morphology, and molecular changes in the heart tissues were analyzed after transverse aortic constriction (TAC) surgery. The mechanisms by which TRIM35 regulates fibroblast phenotypes were elucidated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and RNA sequencing (RNA-Seq). These findings were further validated through the use of adenoviral and adeno-associated viral transfection systems, as well as the mTORC1 inhibitor Rapamycin.
TRIM35 expression is primarily up-regulated in cardiac fibroblasts in both murine and human fibrotic hearts, and responds to TGF-β1 stimulation. Specific deletion of TRIM35 in cardiac fibroblasts significantly improves cardiac fibrosis and hypertrophy. Consistently, the overexpression of TRIM35 promotes fibroblast proliferation, migration, and differentiation. Through paracrine signaling, it induces hypertrophic growth of cardiomyocytes. Mechanistically, we found that TRIM35 interacts with, ubiquitinates, and up-regulates the amino acid transporter SLC7A5, which enhances amino acid transport and activates the mTORC1 signaling pathway. Furthermore, overexpression of SLC7A5 significantly reverses the reduced cardiac fibrosis and hypertrophy caused by conditional knockout of TRIM35.
Our findings demonstrate a novel role of fibroblast-TRIM35 in cardiac remodeling and uncover the mechanism underlying SLC7A5-mediated amino acid transport and mTORC1 activation. These results provide a potential novel therapeutic target for treating cardiac remodeling.
心脏适应性重构是心力衰竭的主要原因之一，其发病机制非常复杂。E3 连接酶三部分包含 35（TRIM35）已被确定为控制细胞生长、免疫反应和代谢的关键调节因子。然而，TRIM35 在心脏重构中的成纤维细胞中的作用仍不清楚。
使用人供体心脏组织验证 TRIM35 的组织特异性表达。使用成纤维细胞特异性 Trim35 基因敲除小鼠（Trim35）研究 TRIM35 在成纤维细胞中的功能。横主动脉缩窄（TAC）手术后分析心脏组织的心脏功能、形态和分子变化。使用液相色谱-串联质谱（LC-MS/MS）和 RNA 测序（RNA-Seq）阐明 TRIM35 调节成纤维细胞表型的机制。通过使用腺病毒和腺相关病毒转染系统以及 mTORC1 抑制剂雷帕霉素进一步验证这些发现。
TRIM35 的表达在人和鼠纤维化心脏中的心肌成纤维细胞中主要上调，并对 TGF-β1 刺激有反应。TRIM35 在心脏成纤维细胞中的特异性缺失可显著改善心脏纤维化和肥大。一致地，TRIM35 的过表达可促进成纤维细胞增殖、迁移和分化。通过旁分泌信号诱导心肌细胞的肥大生长。在机制上，我们发现 TRIM35 与氨基酸转运蛋白 SLC7A5 相互作用、泛素化并上调 SLC7A5，从而增强氨基酸转运并激活 mTORC1 信号通路。此外，SLC7A5 的过表达可显著逆转 TRIM35 条件性敲除引起的心脏纤维化和肥大减少。
我们的研究结果表明成纤维细胞-TRIM35 在心脏重构中的新作用，并揭示了 SLC7A5 介导的氨基酸转运和 mTORC1 激活的机制。这些结果为治疗心脏重构提供了一个潜在的新的治疗靶点。
