Investigating the protective role of the hydrogen sulfide signaling pathways in cardiac and hepatic stress models

Abstract

Hydrogen sulfide (H2S) is now recognized as a pivotal endogenous gasotransmitter involved in cardiovascular and hepatic physiology and pathology. In this work, we investigate the protective role of H2S signaling pathways in cardiac and hepatic stress models, suggesting potential therapeutic applications under oxidative stress and metabolic dysfunction.Doxorubicin (Dox) is an anthracycline chemotherapy agent used to treat a wide range of malignancies. Despite its potent antitumor activity, the clinical use of Dox is limited by dose-dependent cardiotoxicity and hepatotoxicity. Evidence supports the "double-edged sword" effect of H2S in hepatocellular carcinoma cells; however, little data exists on whether, and how, H2S can protect against Dox-induced toxicity. We demonstrate that exogenously added H2S effectively protects against Dox-induced cytotoxicity in hepatic and cardiac cells, primarily through regulating WNT3 signaling and potentially altering the cell-cycle. Additionally, supplementing with H2S exhibited increased viability, decreased cell death, and reduced the production of reactive oxygen species in Dox-treated cells. Transcriptomic analyses revealed extensive modulation in gene expression following Dox-treatment that were partially mitigated by H2S, confirming its broad cytoprotective impact. Next, we evaluated the effect of H2S on phorbol 12-myristate 13-acetate-induced hypertrophy in human cardiomyocytes. H2S reversed key hypertrophic markers and induced transcriptional changes through the modulation of early-response genes, such as ARC and EGR1, highlighting its therapeutic potential in pathological cardiac hypertrophy. Furthermore, we addressed palmitic acid-induced insulin resistance in hepatic and cardiac cells. Although H2S produced only modest transcriptomic changes, it improved metabolic markers, as evidenced by RNA-sequencing analysis. Finally, we elucidated structural differences between the thiol methyltransferases (TMT) TMT1A and TMT1B that methylate hydrogen sulfide and quench its protective properties. This work highlighted critical aromatic residues that differ in the inhibitor selectivity of 2,3-dichloro-α-methylbenzylamine (DCMB). These insights will enable the development of a TMT1B selective inhibitor, advancing our understanding of enzyme specificity and providing a basis for therapeutic modulation of H2S methylation. Overall, this research underscores the multifaceted protective role of H2S, underscoring its significant therapeutic potential in reducing oxidative stress-related diseases.