Key result
Both H2S donors inhibit cardiomyocyte hypertrophy, but only GYY4137 reduces oxidative stress and promotes autophagy.
Why the study?
Sustained cardiac hypertrophy damages the heart, and various H2S donors are potential therapeutics whose effects on ISO-induced hypertrophy, mitochondrial function, and autophagy needed investigation.
Do H2S donors (GYY4137 and BM-112) prevent isoproterenol-induced cardiac hypertrophy and oxidative stress in cardiomyocytes?
Do H2S donors (GYY4137 and BM-112) prevent isoproterenol-induced cardiac hypertrophy and oxidative stress in cardiomyocytes?
The slow H2S releaser GYY4137 effectively prevents isoproterenol-induced cardiomyocyte hypertrophy by reducing oxidative stress and enhancing autophagy, whereas the fast releaser BM-112 only reduces cell size without improving oxidative or autophagic profiles.
GYY4137 but not BM-112 may attenuate hypertrophy via autophagy in models; leaves open translation to human HF.
Cardiac hypertrophy is a compensatory response often associated with cardiovascular diseases. While myocardial hypertrophy provides some advantages at the initial stages of these conditions, sustained hypertrophy can damage the heart, leading to arrhythmia and heart failure. An increasing number of H 2 S donors, with diverse chemical and pharmacological properties, have been identified as potential therapeutic agents against oxidative stress and myocardial hypertrophy, with the possibility of regulating autophagy. The aim of this project was to investigate the effect of H 2 S on isoproterenol (ISO)-induced cardiac hypertrophy and oxidative stress, as well as its impact on mitochondrial function and autophagy. As exogenous H 2 S sources, we employed a newly synthesized fast H 2 S-releasing aspirin derivative (BM-112) and GYY4137 a known slow releasing donor. Our results confirmed that H 2 S was successfully released from BM-112 in a cell culture medium, and each compound enhanced significantly the intracellular level of H 2 S, as measured using the HSip-1 DA probe. Biocompatibility of BM-112 was assessed using MTT assay, which showed no cytotoxic effect on H9c2 at concentrations below 50 µM. Both H 2 S releasing molecules, BM-112 and GYY4137, significantly inhibited ISO-induced hypertrophy in cardiomyocytes, as evidenced by decreased cell size. GYY4137 effectively inhibited ISO-induced oxidative stress (DCF-DA) and mitigated mitochondrial dysfunction (MitoSOX Red and JC-1), whereas BM-112 failed to alleviate these effects. Changes in autophagic protein expressions were analyzed by Western blot, and LC3B/p62 colocalization was visualized with Lysotracker Red. We identified impaired autophagic flux in the presence of ISO and BM-112. However, GYY4137 treatment promoted autophagy beyond basal levels.Taken together, GYY4137, but not BM-112, successfully prevented adrenergic overstimulation-induced hypertrophy by reducing oxidative stress, mitigating mitochondrial dysfunction, and enhancing autophagic flux. • H 2 S was released from BM-112 and GYY4137, increasing intracellular H 2 S levels. • BM-112 showed no cytotoxicity in H9c2 cells at concentrations below 50 µM. • Both H 2 S donors inhibited ISO-induced cardiomyocyte hypertrophy significantly. • GYY4137 reduced ISO-induced oxidative stress and mitochondrial dysfunction. • GYY4137 promoted autophagy, while ISO and BM-112 impaired autophagic flux.
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Gyöngyösi et al. (2025) studied Isoproterenol-induced cardiac hypertrophy. BM-112 and GYY4137 vs. Isoproterenol alone was evaluated on Isoproterenol-induced cardiac hypertrophy, oxidative stress, mitochondrial function, and autophagy. Both H2S donors BM-112 (<50 µM) and GYY4137 significantly inhibited isoproterenol-induced cardiomyocyte hypertrophy, but only GYY4137 reduced oxidative stress and promoted autophagy.
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