The exploration of the pathogenesis and causative relationship of hypertrophic cardiomyopathy mediated by STAT3 through bioinformatics and Mendelian randomization

Abstract

Abstract Purpose Hypertrophic cardiomyopathy (HCM) is a prevalent condition posing a severe threat to human health. This study aims to investigate the expression of STAT3 in HCM and its potential mechanisms. Methods Two sets of data from hypertrophic cardiomyopathy patients and healthy individuals were downloaded from the Gene Expression Omnibus (GEO) database. After batch effect removal and merging, differential analysis of STAT3 between healthy individuals and HCM such as limma and Weighted correlation network analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed for gene function enrichment. In vitro experiments involved constructing angiotensin II (Ang II)-induced H9c2 cardiomyocytes to validate STAT3 expression and explore the impact of hydrogen sulfide(H2S) intervention on improving drug targets for H9c2 cardiomyocyte hypertrophy. Lastly, MR was utilized to explore the causal relationship between STAT3 and HCM. Results STAT3 exhibited high expression in HCM patients. GO analysis indicated enrichment in immune responses, cell proliferation, and transcription. KEGG analysis suggested associations between HCM and pathways like JAK/STAT and NF-kβ. In vitro experiments demonstrated no significant change in STAT3 within Ang II-induced H9c2 cardiomyocytes, with an upregulation of P-STAT3 and hypertrophy-related proteins ANP and BNP. However, these changes were attenuated following H2S intervention. MR showed no causal relationship between STAT3 and HCM. In conclusion, while STAT3 may be associated with HCM occurrence, its expression doesn't exhibit a causal relationship with HCM. The mechanism for STAT3-induced HCM might be linked to increased P-STAT3 levels, and H2S might ameliorate HCM by inhibiting STAT3 phosphorylation.