Similar observations have independently been made for isoproterenol-induced myocardial injury 6, 7, adriamycin-induced cardiomyopathy 8 and spontaneously hypertensive rats 9. Amongst some notable evidences, the circulating and myocardial levels of H 2S were observed to be significantly (nearly 60%) lower in animals subjected to transverse aortic constriction-culminating in pressure overload, hypertrophy and heart failure 5. Some recent studies (from both animal as well as human studies) have, interestingly, revealed a strong association between multiple cardio-pathological states and hydrogen sulfide (H 2S)-a gaseous messenger endogenously produced through elaborate enzyme systems in mammalian cells 4. Not surprisingly, therefore, numerous therapeutic targets/molecules with potential anti-hypertrophy effects have been identified 1 and are being studied for their mechanistic basis. It is associated with multiple cardio-vascular diseases and is a robust prognostic marker of risk for chronic heart failure 3. 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. ![]() Our data, thus, revealed H 2S as a critical endogenous regulator of cardiac metabolic circuitry, and also mechanistic basis for its anti-hypertrophic effects. 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 H 2S augmentation. Utilizing both cellular and animal model systems, we show that H 2S-induced elevated G6PD activity is critical for the suppression of cardiac hypertrophy in response to adrenergic overstimulation. 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 H 2S. Interestingly, unbiased global transcriptome sequencing analysis revealed an integrated metabolic circuitry, centrally linked by NADPH homeostasis, as the direct target of intracellular H 2S augmentation. The preservation of intracellular H 2S levels under these conditions strongly suppressed hypertrophic responses to adrenergic overstimulation, thus suggesting its intrinsic role in this process. Here, we show that β-adrenergic receptor (β-AR) overstimulation, known to produce hypertrophic effects in cardiomyocytes, rapidly decreased endogenous H 2S levels. ![]() The molecular niche of H 2S in normal or diseased cardiac cells is, however, sparsely understood. Hydrogen Sulfide (H 2S), recently identified as the third endogenously produced gaseous messenger, is a promising therapeutic prospect for multiple cardio-pathological states, including myocardial hypertrophy.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |