THRA deletion exacerbates myocardial injury and affects ferroptosis-related pathways in PTU-induced hypothyroid mice via GATA4 regulation
Hypothyroidism, a prevalent endocrine disorder, frequently gives rise to myocardial injury as a complication. Mutations in the thyroid hormone receptor alpha (THRA) gene can lead to thyroid hormone resistance and hypothyroidism. However, the role of THRA in myocardial injury associated with hypothyroidism remains elusive. This study aimed to investigate the function of THRA in myocardial injury in a propylthiouracil (PTU)-induced hypothyroid mouse model and its underlying mechanisms. A PTU-induced hypothyroid mouse model was established to observe the effects of THRA gene knockout on physiological status, thyroid function, myocardial injury markers, myocardial pathology, apoptosis, ferroptosis, and the expression of GATA4, an upstream regulator of THRA. Comprehensive assessments were conducted using ELISA, biochemical analysis, immunohistochemistry, Western blot, qPCR, immunofluorescence, and dual-luciferase reporter gene assays. THRA knockout exacerbated myocardial injury in hypothyroid mice, manifested as impaired myocardial function, fibrosis, increased cardiomyocyte apoptosis, and ferroptosis. Further exploration revealed that GATA4, an upstream regulator of THRA, enhanced THRA promoter activity by binding to its promoter, thereby promoting THRA transcription. Moreover, the PI3K/AKT signaling pathway, as a downstream target of THRA, played a pivotal role in myocardial ferroptosis. THRA exerts a protective role in myocardial injury in hypothyroid mice, and its absence aggravates myocardial injury and ferroptosis. GATA4 serves as an upstream regulator of THRA, and THRA may influence ferroptosis through the PI3K/AKT signaling pathway. This study sheds light on the mechanistic role of THRA in myocardial injury associated with hypothyroidism, providing a theoretical foundation for the development of targeted therapeutic strategies.