Hydrogen sulfide attenuates PMA-Induced hypertrophy in human cardiomyocytes by modulating gene expression and...

Cardiac hypertrophy is a physiological response to maintain cardiac output by increasing left ventricular mass and thickening the left ventricular wall. Hydrogen sulfide (H₂S) is an endogenous gasotransmitter and plays important roles in cardiovascular diseases, however, its role in hypertrophy remains unclear. In this study, we used phorbol 12-myristate 13-acetate (PMA) to induce hypertrophy in human ventricular cardiomyocytes (hCM) and investigated the effect of H₂S on hypertrophic cells. PMA treatment induced hypertrophy, enlarged cell size, and elevated the hypertrophic marker BNP/NPPB. These changes were accompanied by higher endogenous H₂S levels and upregulation of H₂S-producing enzymes, particularly with cystathionine γ-lyase (CSE) at both RNA and protein levels. Supplementation with sodium hydrosulfide (NaSH), an H₂S donor, significantly reduced BNP/NPPB expression. RNA sequencing identified more than 3,600 differentially expressed genes (DEG) altered by H₂S in PMA-treated cells. KEGG enrichment revealed that H₂S modulates AMPK, MAPK, GnRH signaling, focal adhesion, and apoptosis pathways, while a protein-protein interaction network highlighted the immediate-early genes such as ARC and EGR1 as central hubs in the anti-hypertrophic network. Since thiol methylation can limit endogenous H₂S levels, we examined changes in the expression of thiol methyltransferases TMT1A and TMT1B, which convert H₂S to methanethiol (CH₃SH). Hypertrophic cells exhibited decreased CH₃SH levels and reduced TMT expression. Supplementation of exogenous CH₃SH exacerbated hypertrophy while triggering compensatory upregulation of H₂S-producing enzymes. Collectively, our findings indicate that H₂S attenuates hypertrophy in hCM by modulating stress-response signaling and suppressing its own methylation. These results support targeting H₂S metabolism as a potential therapeutic strategy for cardiac hypertrophy.