Dusp14-Mediated Dephosphorylation of MLKL Protects Against Cardiomyocyte Necroptosis in Hypothyroidism-Induced Heart Failure.

Abstract

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. In this study, a mouse model of hypothyroidism-induced heart failure was established through the administration of propylthiouracil. <i>Dusp14</i> 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. 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, <i>Dusp14</i> 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). 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.