Dusp14介导的MLKL去磷酸化可预防甲状腺功能减退所致心力衰竭中的心肌细胞坏死性凋亡。
Dusp14-Mediated Dephosphorylation of MLKL Protects Against Cardiomyocyte Necroptosis in Hypothyroidism-Induced Heart Failure.
作者信息
Zheng Yitian, Cao Yueyue, Wang Wenyao, Tong Yicheng, Wang Shuaixing, Li Chen, Zhao Mingming, Song Yao, Wang Yuan-Geng-Shuo, Qi Jiating, Wu Chao, Yang Jie, Zheng Jilin, Gao Jun, Wang Jingjia, Yang Qing, Liu Gang, Zhao Jiajun, Zhang Yan, Xiao Han, Zhang You-Yi, Tang Yi-Da
机构信息
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China (Y. Zheng, Y.C., W.W., Y.T., C.L., M.Z., Y.S., Y.-g.-s.W., J.Q., C.W., J.Y., J. Zheng, J.G., J.W., Y. Zhang, H.X., Y.-Y.Z., Y.-D.T.).
Beijing Key Laboratory of Clinical Evaluation of Cardiovascular-Kidney-Metabolic and Immuno-Inflammatory Innovative Drugs and Medical Devices, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China (Y. Zheng, Y.C., W.W., Y.T., C.L., M.Z., Y.S., Y.-g.-s.W., J.Q., C.W., J.Y., J. Zheng, J.G., J.W., Y. Zhang, H.X., Y.-Y.Z., Y.-D.T.).
出版信息
Circulation. 2025 Jun 24;151(25):1797-1813. doi: 10.1161/CIRCULATIONAHA.125.074353. Epub 2025 May 13.
BACKGROUND
Hypothyroidism leads to multiple organ dysfunction, with the heart the most affected. However, the pathologic mechanism of hypothyroidism-induced heart failure remains to be completely elucidated. Thyroid hormone replacement therapy enhances myocardium systolic function but increases the occurrence of arrythmias. There is an urgent need to explore these mechanisms in detail and to discover and develop drugs that can target and manage heart failure in patients with hypothyroidism.
METHODS
In this study, a mouse model of hypothyroidism-induced heart failure was established through the administration of propylthiouracil. knockout mice were generated, and adeno-associated virus-mediated cardiomyocyte-specific overexpression of Dusp14 (dual specificity phosphatase 14) was used in combination with related cellular experiments to investigate the protective effects of Dusp14 on hypothyroidism-induced heart failure. Further analyses confirmed the crucial involvement of necroptosis in the pathogenesis of hypothyroidism-induced heart failure, and demonstrated the protective role of Dusp14 in modulating necroptosis. In addition, a novel small molecule compound that effectively regulates Dusp14 activity in vitro was identified through molecular docking, providing a potential therapeutic avenue.
RESULTS
Dusp14 regulates necroptosis and mitigates hypothyroidism-induced heart failure. Myocardial tissue sections from mice in the hypothyroidism group showed positive Evans blue dye staining, and the serum levels of the myocardial injury marker lactate dehydrogenase were significantly higher compared with the euthyroid group (n=8). In addition, phosphorylation levels of the necroptosis marker MLKL (mixed lineage kinase domain-like protein) were significantly elevated, indicating the activation of necroptosis (n=8). These findings suggest that myocardial necroptosis is activated during hypothyroidism. Myocardial-specific overexpression of Dusp14 reduced myocardial necroptosis and improved myocardial contractile function in hypothyroid mice (n=8). In contrast, knockout exacerbated myocardial contractile dysfunction and necroptosis in these mice (n=5-7). These results indicate that Dusp14 alleviates hypothyroidism-induced heart failure by inhibiting necroptosis. P077-0472, a small molecule compound, was identified as an activator of Dusp14, which could inhibit cardiomyocyte necroptosis from hypothyroidism (n=6).
CONCLUSIONS
Dusp14 inhibits cardiomyocyte necroptosis from hypothyroidism and consequently rescues damaged cardiomyocytes. P077-0472, a novel small molecule compound that activates the dephosphorylation function of Dusp14, could inhibit cardiomyocyte necroptosis from hypothyroidism.
背景
甲状腺功能减退会导致多器官功能障碍，其中心脏受影响最为严重。然而，甲状腺功能减退所致心力衰竭的病理机制仍有待完全阐明。甲状腺激素替代疗法可增强心肌收缩功能，但会增加心律失常的发生率。迫切需要详细探究这些机制，并发现和开发能够靶向治疗甲状腺功能减退患者心力衰竭的药物。
方法
在本研究中，通过给予丙硫氧嘧啶建立甲状腺功能减退所致心力衰竭的小鼠模型。构建基因敲除小鼠，并将腺相关病毒介导的心肌细胞特异性过表达双特异性磷酸酶14（Dusp14）与相关细胞实验相结合，以研究Dusp14对甲状腺功能减退所致心力衰竭的保护作用。进一步分析证实坏死性凋亡在甲状腺功能减退所致心力衰竭发病机制中起关键作用，并证明了Dusp14在调节坏死性凋亡中的保护作用。此外，通过分子对接鉴定出一种在体外有效调节Dusp14活性的新型小分子化合物，为潜在的治疗途径提供了依据。
结果
Dusp14调节坏死性凋亡并减轻甲状腺功能减退所致的心力衰竭。甲状腺功能减退组小鼠的心肌组织切片伊文思蓝染料染色呈阳性，与甲状腺功能正常组相比，心肌损伤标志物乳酸脱氢酶的血清水平显著升高（n = 8）。此外，坏死性凋亡标志物混合谱系激酶结构域样蛋白（MLKL）的磷酸化水平显著升高，表明坏死性凋亡被激活（n = 8）。这些发现提示甲状腺功能减退期间心肌坏死性凋亡被激活。在甲状腺功能减退的小鼠中，心肌特异性过表达Dusp14可减少心肌坏死性凋亡并改善心肌收缩功能（n = 8）。相比之下，基因敲除加剧了这些小鼠的心肌收缩功能障碍和坏死性凋亡（n = 5 - 7）。这些结果表明，Dusp14通过抑制坏死性凋亡减轻甲状腺功能减退所致的心力衰竭。小分子化合物P077 - 0472被鉴定为Dusp14的激活剂，它可以抑制甲状腺功能减退引起的心肌细胞坏死性凋亡（n = 6）。
结论
Dusp14抑制甲状腺功能减退引起的心肌细胞坏死性凋亡，从而挽救受损的心肌细胞。新型小分子化合物P077 - 0472可激活Dusp14的去磷酸化功能，抑制甲状腺功能减退引起的心肌细胞坏死性凋亡。
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