HINT2 Protects Against Pressure Overload-induced Cardiac Remodeling Through Mitochondrial Pathways

Histidine triad nucleotide-binding protein 2 (HINT2) is an enzyme found in mitochondria that functions as nucleotide hydrolase and transferase. Prior studies have demonstrated that HINT2 plays a crucial role in ischemic heart disease but the significance of HINT2 in cardiac hypertrophy remains unknown. Therefore, the current study aims to determine the role of HINT2 in cardiac remodeling. HINT2 expression was found to be lower in failing hearts and hypertrophic cardiomyocytes. The mice that overexpressed HINT2 exhibited reduced myocytes hypertrophy and cardiac dysfunction in response to stress. Conversely, the deficiency of HINT2 in the heart of mice resulted in a worsened hypertrophic phenotype. Further analysis indicated that the upregulated genes were primarily associated with the oxidative phosphorylation and mitochondrial complex I pathway in the HINT2-overexpressed mice after aortic banding (AB) treatment. This suggests that HINT2 upregulated the expression of NDUFs genes. In cellular studies, the protective effect of overexpressing HINT2 was nullified. Lastly, we predicted that THRB might regulate HINT2 transcriptional activity. To conclusion, the current study showcased that HINT2 alleviates pressure overload-induced cardiac hypertrophy by depending on the activity and assembly of mitochondrial complex I. Thus, targeting HINT2 could be a novel therapeutic intervention for reducing cardiac remodeling. To understand the protective effects of HINT2, we performed RNA-seq assays on HINT2-TG mouse hearts and NTG hearts after AB treatment.