Glucose-6-phosphate dehydrogenase is critical for suppression of cardiac hypertrophy by H₂S

Hydrogen Sulfide (H₂S), recently identified as the third endogenously produced gaseous messenger, is a promising therapeutic prospect for multiple cardio-pathological states, including myocardial hypertrophy. The molecular niche of H₂S in normal or diseased cardiac cells is, however, sparsely understood. Here, we show that β-adrenergic receptor (β-AR) overstimulation, known to produce hypertrophic effects in cardiomyocytes, rapidly decreased endogenous H₂S levels. The preservation of intracellular H₂S levels under these conditions strongly suppressed hypertrophic responses to adrenergic overstimulation, thus suggesting its intrinsic role in this process. Interestingly, unbiased global transcriptome sequencing analysis revealed an integrated metabolic circuitry, centrally linked by NADPH homeostasis, as the direct target of intracellular H₂S augmentation. Within these gene networks, glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme (producing NADPH) in pentose phosphate pathway, emerged as the critical node regulating cellular effects of H₂S. Utilizing both cellular and animal model systems, we show that H₂S-induced elevated G6PD activity is critical for the suppression of cardiac hypertrophy in response to adrenergic overstimulation. We also describe experimental evidences suggesting multiple processes/pathways involved in regulation of G6PD activity, sustained over extended duration of time, in response to endogenous H₂S augmentation. Our data, thus, revealed H₂S as a critical endogenous regulator of cardiac metabolic circuitry, and also mechanistic basis for its anti-hypertrophic effects.