Pharmacological activation and genetic manipulation of cystathionine beta-synthase alter circulating levels of homocysteine and hydrogen sulfide in mice
2011
Abstract Hydrogen sulfide (H 2 S) is a recently discovered gasotransmitter found in mammalian tissues and blood. Treatment with H 2 S donor molecules has shown promising results in preclinical models of inflammatory and cardiovascular diseases. Augmentation of H 2 S levels thus holds promise as a novel therapeutic approach for treatment of disease in man. Cystathionine β-synthase (CBS) has been shown to catalyze H 2 S production in vitro . CBS enzyme activity is allosterically regulated by the endogenous activator S -adenosyl methionine. This mode of regulation suggests the possibility for designing a small molecule activator of CBS to enhance H 2 S production. This hypothesis, however, has not been directly tested in vivo . We show here that CBS contributes significantly to endogenous H 2 S production in mice: adenovirus mediated over expression of CBS in the liver significantly increased circulating levels of H 2 S, whereas CBS deficiency resulted in reduced levels. We demonstrate that CBS enzyme from endogenous sources can be activated by S -adenosyl methionine to a greater extent compared to recombinant enzyme, suggesting greater potential for activation than previously anticipated. Importantly, we show that circulating H 2 S levels are increased by pharmacological activation of CBS in vivo ; i.e. in the presence of the endogenous activator. Together, our data demonstrate that CBS activity partially regulates endogenous H 2 S in mice, and suggest that pharmacological activation of CBS is a promising approach for enhancing endogenous production of H 2 S for the treatment of cardiovascular and other diseases.
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