HINT2 protects against pressure overload‐induced cardiac remodelling through mitochondrial pathways

• Published in: Journal of cellular and molecular medicine Vol. 28; no. 8; pp. e18276 - n/a
• Main Authors: Zhang, Nan, Zhou, Zi‐Ying, Meng, Yan‐Yan, Liao, Hai‐Han, Mou, Shan‐Qi, Lin, Zheng, Yan, Han, Chen, Si, Tang, Qi‐Zhu
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.04.2024; John Wiley and Sons Inc
• Subjects: Animals; Aorta; cardiac remodelling; Cardiomyocytes; Coronary vessels; Dehydrogenases; Electron transport chain; Electron Transport Complex I - genetics; Heart; Heart diseases; HINT2; Histidine; Hydrolases; Hypertrophy; Ischemia; Laboratory animals; Mice; Mitochondria; mitochondrial complex I; Mitochondrial Proteins - genetics; Myocytes; NADH dehydrogenase; NADH dehydrogenase (ubiquinone); NADH-ubiquinone oxidoreductase; NDUFs; Nucleotides; Original; Oxidative phosphorylation; Peptides; Phenotypes; Phosphorylation; Proteins; Rotenone; Ventricular Remodeling - genetics; United States > US; cardiac remodelling; HINT2; mitochondrial complex I; hypertrophy; NDUFs
• DOI: 10.1111/jcmm.18276
• ISSN: 1582-1838

Histidine triad nucleotide‐binding protein 2 (HINT2) is an enzyme found in mitochondria that functions as a nucleotide hydrolase and transferase. Prior studies have demonstrated that HINT2 plays a crucial role in ischemic heart disease, but its importance in cardiac remodelling remains unknown. Therefore, the current study intends to determine the role of HINT2 in cardiac remodelling. HINT2 expression levels were found to be lower in failing hearts and hypertrophy cardiomyocytes. The mice that overexpressed HINT2 exhibited reduced myocyte hypertrophy and cardiac dysfunction in response to stress. In contrast, the deficiency of HINT2 in the heart of mice resulted in a worsening hypertrophic phenotype. Further analysis indicated that upregulated genes were predominantly associated with the oxidative phosphorylation and mitochondrial complex I pathways in HINT2‐overexpressed mice after aortic banding (AB) treatment. This suggests that HINT2 increases the expression of NADH dehydrogenase (ubiquinone) flavoprotein (NDUF) genes. In cellular studies, rotenone was used to disrupt mitochondrial complex I, and the protective effect of HINT2 overexpression was nullified. Lastly, we predicted that thyroid hormone receptor beta might regulate HINT2 transcriptional activity. To conclusion, the current study showcased that HINT2 alleviates pressure overload‐induced cardiac remodelling by influencing the activity and assembly of mitochondrial complex I. Thus, targeting HINT2 could be a novel therapeutic strategy for reducing cardiac remodelling.