Abstract
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.
Highlights
The hypertrophic growth of myocardium—conventionally thought to be a benign, compensatory response to increased cardiac workload—is increasingly being categorized as a pathological state warranting timely and effective therapeutic intervention[1,2]
Adrenergic stimulation rapidly decreases endogenous H2S in cardiomyocytes β-adrenergic receptor (β-AR) overstimulation is known to culminate in left ventricular hypertrophy
In view of aforementioned inverse association between myocardial H2S levels and cardiac hypertrophy/dysfunction, we sought to investigate if β-AR stimulation per se can modulate endogenous H2S levels in cardiomyocytes
Summary
The hypertrophic growth of myocardium—conventionally thought to be a benign, compensatory response to increased cardiac workload—is increasingly being categorized as a pathological state warranting timely and effective therapeutic intervention[1,2]. Exogenous donors or strategies (employing genetic tools) to augment endogenous levels of H2S appear to manifest ‘‘cardio-protective’’ effects during multiple pathological conditions affecting heart[5,10] Despite such compelling evidences, and gradual appraisal of H2S as an authentic signaling molecule[11], the cellular niche of this key messenger in normal or diseased myocardium remains incompletely understood. It is tempting to speculate that cue-dependent downregulation of endogenous H2S could per se propel specific signaling pathways and culminate in cardio-pathological effects—a possible reason why therapeutic modulation of endogenous H2S produces distinctive cardio-protective effects This proposition draws support from certain known effects of H2S in cardiovascular system, including preservation of mitochondrial function[14], regulation of Nrf-2 signaling cascade[15] and endothelial nitric oxide synthase (eNOS) activity[16] (through sulfhydration of its specific cysteine residues). The utilization of an exogenous H2S donor, prior to adrenergic stimulation, prevented this effect and strongly counteracted hypertrophic progression, suggesting an intrinsic role of
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