Aims Cardiac remodelling is a common pathophysiological process in the development of various cardiovascular diseases, but there is still a lack of effective interventions. Tumour necrosis receptor-associated factor 7 (TRAF7) belongs to the tumour necrosis factor receptor-associated factor family and plays an important role in biological processes. Previous studies have shown that TRAF7 mutations lead to congenital defects and malformations of the heart. However, the molecular mechanisms of TRAF7 in the underlying pathogenesis of pathological cardiac hypertrophy remain unknown. We aim to study the molecular mechanisms and effects of TRAF7 in cardiac remodelling and whether it has the potential to become a therapeutic target for cardiac remodelling. Methods and results The pressure overload–induced cardiac hypertrophy model in mice was established via transverse aortic constriction (TAC) surgery, and cardiomyocytes were treated with phenylephrine (PE) to induce hypertrophic phenotype. Levels of cardiac dysfunction and remodelling were measured with echocardiography and tissue or cell staining. RNA sequencing, western blot, qRT–PCR, co-immunoprecipitation, and in vivo ubiquitination assays were used to explore the molecular mechanisms. The results showed that the expression of TRAF7 increased gradually during the development of hypertrophy. Accordingly, TRAF7 significantly exacerbated the PE-induced enlargement of primary neonatal Sprague-Dawley rat cardiomyocytes, whereas TRAF7 knockdown alleviated the hypertrophic phenotype in primary cardiomyocytes. Cardiac-specific overexpression of TRAF7 accelerated hypertrophic phenotype in mice and cardiac-specific Traf7 conditional knockout mice improved hypertrophic phenotype induced by TAC. Mechanistically, TRAF7 directly interacted with apoptosis signal-regulating kinase-1 (ASK1) and promoted ASK1 phosphorylation by mediating the K63-linked ubiquitination of ASK1 in response to PE stimulation, which then promoted ASK1 activation and downstream signalling during cardiac hypertrophy. Notably, the pro-hypertrophic effect of TRAF7 was largely blocked by GS4997 in vitro and cardiac-specific Ask1 conditional knockout in vivo. Conclusion In summary, we identified TRAF7 as an essential regulator during cardiac hypertrophy, and modulation of the regulatory axis between TRAF7 and ASK1 could be a novel therapeutic strategy to prevent this pathological process.

中文翻译：

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心脏肿瘤坏死因子受体相关因子 7 介导细胞凋亡信号调节激酶 1 的泛素化并加重心脏肥大


目的 心脏重塑是各种心血管疾病发展中常见的病理生理过程，但目前仍缺乏有效的干预措施。肿瘤坏死受体相关因子 7 （TRAF7） 属于肿瘤坏死因子受体相关因子家族，在生物过程中起重要作用。既往研究表明，TRAF7 突变导致先天性缺陷和心脏畸形。然而，TRAF7 在病理性心脏肥大的潜在发病机制中的分子机制仍然未知。我们旨在研究 TRAF7 在心脏重塑中的分子机制和作用，以及它是否有潜力成为心脏重塑的治疗靶点。方法和结果 通过横主动脉缩窄 （TAC） 手术建立压力超负荷诱导的小鼠心脏肥大模型，用去氧肾上腺素 （PE） 处理心肌细胞以诱导肥大表型。通过超声心动图和组织或细胞染色测量心功能不全和重塑的水平。采用 RNA 测序、 western blot、 qRT-PCR、免疫共沉淀和体内泛素化测定来探索分子机制。结果表明，TRAF7 的表达在肥大发展过程中逐渐增加。因此，TRAF7 显着加剧了 PE 诱导的原代新生 Sprague-Dawley 大鼠心肌细胞的增大，而 TRAF7 敲除减轻了原代心肌细胞的肥大表型。TRAF7 的心脏特异性过表达加速了小鼠的肥大表型，心脏特异性 Traf7 条件性敲除小鼠改善了 TAC 诱导的肥大表型。 从机制上讲，TRAF7 直接与细胞凋亡信号调节激酶 1 （ASK1） 相互作用，并通过介导 ASK1 响应 PE 刺激的 K63 连接泛素化来促进 ASK1 磷酸化，然后促进心脏肥大期间的 ASK1 激活和下游信号传导。值得注意的是，TRAF7 的促肥大作用在很大程度上被体外 GS4997 和体内心脏特异性 Ask1 条件敲除阻断。结论 综上所述，我们确定 TRAF7 是心脏肥大过程中的重要调节因子，调节 TRAF7 和 ASK1 之间的调节轴可能是预防这种病理过程的新型治疗策略。