H2S regulates redox signaling downstream of cardiac β-adrenergic receptors in a G6PD-dependent manner.

Stimulating β-adrenergic receptors (β-AR) culminates in pathological hypertrophy - a condition underlying multiple cardiovascular diseases (CVDs). The ensuing signal transduction network appears to involve mutually communicating phosphorylation-cascades and redox signaling modules, although the regulators of redox signaling processes remain largely unknown. We previously showed that H2S-induced Glucose-6-phosphate dehydrogenase (G6PD) activity is critical for suppressing cardiac hypertrophy in response to adrenergic stimulation. Here, we extended our findings and identified novel H2S-dependent pathways constraining β-AR-induced pathological hypertrophy. We demonstrated that H2S regulated early redox signal transduction processes - including suppression of cue-dependent production of reactive oxygen species (ROS) and oxidation of cysteine thiols (R-SOH) on critical signaling intermediates (including AKT1/2/3 & ERK1/2). Consistently, the maintenance of intracellular levels of H2S dampened the transcriptional signature associated with pathological hypertrophy upon β-AR-stimulation, as demonstrated by RNA-seq analysis. We further prove that H2S remodels cell metabolism by promoting G6PD activity to enforce changes in the redox state that favor physiological cardiomyocyte growth over pathological hypertrophy. Thus, our data suggest that G6PD is an effector of H2S-mediated suppression of pathological hypertrophy and that the accumulation of ROS in the G6PD-deficient background can drive maladaptive remodeling. Our study reveals an adaptive role for H2S relevant to basic and translational studies. Identifying adaptive signaling mediators of the β-AR-induced hypertrophy may reveal new therapeutic targets and routes for CVD therapy optimization.