Pharmacological activation and genetic manipulation of cystathionine beta-synthase alter circulating levels of homocysteine and hydrogen sulfide in mice.
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.
Jensen
Kristian K
KK
Department of Cardiovascular Diseases, Merck & Co., Inc., Rahway, NJ 07065, USA. kristian_jensen@merck.com
Geoghagen
Neil S
NS
Jin
Lan
L
Holt
Tom G
TG
Luo
Qi
Q
Malkowitz
Lorraine
L
Ni
Weihua
W
Quan
Shuo
S
Waters
M Gerard
MG
Zhang
Aiwu
A
Zhou
Heather H
HH
Cheng
Kang
K
Luo
Ming-Juan
MJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003541:Cystathionine beta-Synthase / Q000235:genetics* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005818:Genetic Engineering; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D006862:Hydrogen Sulfide / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000494:pharmacology
D011994:Recombinant Proteins; D006710:Homocysteine; D012436:S-Adenosylmethionine; D003541:Cystathionine beta-Synthase; D006862:Hydrogen Sulfide