Duan Fengqi, Li Huangjing, Lu Bo, Wang Xiaobo, Xu Xiaojun
Department of Hematology, The Seventh Affiliated Hospital of Sun Yat-Sen University, Sun Yat-Sen University, No. 628 Zhenyuan Road, Shenzhen, 518106, Guangdong, China.
Department of Pathophysiology, School of Medicine, Sun Yat-Sen University, Shenzhen, 518106, Guangdong, China.
Inflammation. 2024 Dec 13. doi: 10.1007/s10753-024-02217-w.
Tripartite motif-containing protein 31 (Trim31) is known to be involved in various pathological conditions, including heart diseases. Nonetheless, its specific involvement in heart failure (HF) has yet to be determined. In this study, we examined the function and mechanism of Trim31 in HF by using mice with cardiac-specific knockout (cKO) of Trim31. The HF mouse model was induced via the subcutaneous injection of isoproterenol (ISO). We observed a decrease in Trim31 expression in the heart tissues of mice with HF. Compared with wild-type (WT) mice, Trim31 cKO mice presented more severe characteristics of HF, including worsened cardiac dysfunction, hypertrophy, and fibrosis. However, these symptoms in Trim31 cKO mice were significantly reversed when they received an intramyocardial injection of recombinant adeno-associated virus (AAV) expressing Trim31. Excessive activation of the NLRP3 inflammasome, manifested by increased levels of NLRP3, ASC, cleaved Caspase-1, cleaved GSDMD, IL-1β, and IL-18, was observed in Trim31 cKO mice with HF. However, Trim31 overexpression effectively reversed the NLRP3 inflammasome activation in Trim31 cKO mice with HF. Selective inhibition of the NLRP3 inflammasome with the NLRP3 inhibitor MCC950 effectively reversed the worsened cardiac dysfunction, hypertrophy, and fibrosis observed in Trim31 cKO mice with HF. Overall, the findings from this study reveal a crucial role of Trim31 in HF. Trim31 deficiency may contribute to the progression of HF by promoting cardiac hypertrophy, fibrosis, and inflammation by facilitating the activation of the NLRP3 inflammasome. Therefore, Trim31 may hold significant potential as a therapeutic target for the treatment of HF.
已知含三联基序的蛋白31（Trim31）参与多种病理状况，包括心脏病。然而，其在心力衰竭（HF）中的具体作用尚未确定。在本研究中，我们通过使用心脏特异性敲除（cKO）Trim31的小鼠来研究Trim31在HF中的功能和机制。HF小鼠模型通过皮下注射异丙肾上腺素（ISO）诱导产生。我们观察到HF小鼠心脏组织中Trim31表达下降。与野生型（WT）小鼠相比，Trim31 cKO小鼠表现出更严重的HF特征，包括心脏功能障碍、肥大和纤维化加重。然而，当Trim31 cKO小鼠接受心肌内注射表达Trim31的重组腺相关病毒（AAV）时，这些症状得到了显著逆转。在患有HF的Trim31 cKO小鼠中观察到NLRP3炎性小体过度激活，表现为NLRP3、ASC、裂解的半胱天冬酶-1、裂解的Gasdermin D、IL-1β和IL-18水平升高。然而，Trim31过表达有效地逆转了患有HF的Trim31 cKO小鼠中NLRP3炎性小体的激活。用NLRP3抑制剂MCC950选择性抑制NLRP3炎性小体有效地逆转了在患有HF的Trim31 cKO小鼠中观察到的心脏功能障碍、肥大和纤维化加重。总体而言，本研究结果揭示了Trim31在HF中的关键作用。Trim31缺乏可能通过促进心脏肥大、纤维化和炎症，促进NLRP3炎性小体的激活，从而导致HF的进展。因此，Trim31作为HF治疗的潜在治疗靶点可能具有重要意义。
