Abstract
ABSTRACTIn addition to its role in the endogenous synthesis of cysteine, cystathionine gamma-lyase (CGL) is a major physiological source of the vasorelaxant hydrogen sulfide. Cgl null mice are potentially useful for studying the influence of this compound upon vascular tone and endothelial function. Here, we confirm a previous report that female Cgl null mice exhibit an approximate 45-fold increase in plasma total homocysteine compared to wild type controls. This level of homocysteine is approximately 3.5-fold higher than that observed in male Cgl null mice and is essentially equivalent to that observed in mouse models of cystathionine beta synthase deficient homocystinuria. Cgl null mice of both sexes exhibited decreased expression of methylenetetrahydrofolate reductase and cysteinesulfinate decarboxylase compared to WT controls. Female Cgl null mice exhibited a sex-specific induction of betaine homocysteine S-methyltransferase and methionine adenosyltransferase 1, alpha and a 70% decrease in methionine synthase expression accompanied by significantly decreased plasma methionine. Decreased plasma cysteine levels in female Cgl null mice were associated with sex-specific dysregulation of cysteine dioxygenase expression. Comparative histological assessment between cystathionine beta-synthase and Cgl null mice indicated that the therapeutic potential of cystathionine against liver injury merits possible further investigation. Collectively, our data demonstrates the importance of considering sex when investigating mouse models of inborn errors of metabolism and indicate that while female Cgl null mice are of questionable utility for studying the physiological role of hydrogen sulfide, they could serve as a useful model for studying the consequences of methionine synthase deficiency and the methylfolate trap.
Highlights
Cgl null female but not male mice exhibit severely elevated levels of plasma total homocysteine (tHcy) In order to more fully characterize the previously reported sexdifferences in tHcy in Cgl null mice, we measured plasma levels of tHcy and cystathionine, in male and female wild type (WT) and Cgl null mice (n=10 for each group) as described in the Materials and Methods section. Both male and female Cgl mice exhibited massive accumulation of plasma cystathionine compared to WT controls but showed no significant difference as a consequence of sex (P=0.1581)
Male Cgl null mice showed an approximate 10-fold increase in plasma tHcy compared to WT controls at a level comparable to both male and female mice treated with the cystathionine gamma-lyase (CGL) inhibitor compound PPG (Fig. 1B) and essentially identical to levels reported previously for male mice from this model (Yang et al, 2008)
DISCUSSION relatively subtle changes in plasma tHcy as a consequence of sex hormone metabolism been reported previously (Giltay et al, 1998; Mantueffel-Cymborowska et al, 1992; Oktenli et al, 2003), to our knowledge, the Cgl null mouse model is the only reported case of profound sex-specific alterations in Hcy metabolism and serves to highlight the fact that sex is rarely considered in animal models of inborn errors of metabolism
Summary
In addition to a role in endogenous cysteine synthesis, CGL catalyzes an α,β-disulfide elimination reaction that results in the production of pyruvate, ammonia and thiocysteine This latter compound may react with other thiol compounds to generate hydrogen sulfide (H2S). A previously described Cgl null mouse model (Yang et al, 2008) would seem an ideal system to investigate this hypothesis but a previous report has indicated that female Cgl null mice incur severely elevated plasma total homocysteine (tHcy) This compound has the potential to form mixed disulfides with the H2S donor compound cysteine and interfere with studies designed to assess the potential vasorelaxant role of endogenously generated H2S (Yang et al, 2008). The reason for this female-specific biochemical anomaly and possible changes to other relevant metabolites has to date, remained uninvestigated
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