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TSH promotes right ventricle hypertrophy and energy metabolism remodeling in PAH mice

Feifei Shao,Wenyan Zhang,Xiaotao Li,Ziqi Han,Xiao Lu,Cuixia Gao,Limin Tian

Published 2025 in Endocrine Connections

ABSTRACT

Subclinical hypothyroidism is characterized by elevated thyroid stimulating hormone (TSH) levels and normal FT4, and is associated with an increased risk of cardiovascular diseases, but its specific impacts on the right ventricle and underlying mechanisms remain unclear. This study aimed to investigate the direct role of TSH signaling through its receptor in right ventricular hypertrophy and energy metabolism remodeling. A model of pulmonary arterial hypertension-induced right ventricular injury was created in male cardiomyocyte-specific TSH receptor knockout mice and control mice using Sugen5416 combined with hypoxia (10% O2). Cardiac function was assessed via echocardiography, while histological and molecular changes were examined through staining techniques, quantitative PCR, and Western blot. Metabolic alterations were quantified using ultra-high-performance liquid chromatography-tandem mass spectrometry. Results demonstrated that pulmonary hypertension induced right ventricular dysfunction, hypertrophy, and metabolic dysregulation in control mice, characterized by impaired systolic and diastolic function, increased glycolytic enzyme expression, lactate accumulation, and reduced ATP levels. These pathological changes were significantly attenuated in TSH receptor knockout mice. In vitro, TSH treatment promoted hypertrophic marker expression and shifted metabolic activity toward glycolysis in H9c2 cardiomyocytes. In conclusion, our in vivo and in vitro experiments demonstrate that TSH promotes cardiomyocyte hypertrophy and upregulates the glycolytic pathway. These findings reveal a direct contribution of elevated TSH to right ventricular injury and may offer novel mechanistic insights into right ventricular impairment associated with subclinical hypothyroidism.

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