Disease relevance of Cbs

• Hyperhomocysteinemia accelerates atherosclerosis in cystathionine beta-synthase and apolipoprotein E double knock-out mice with and without dietary perturbation [1].
• Deficiency in cystathionine beta synthase (CBS) leads to high plasma homocysteine concentrations and causes hyperhomocysteinemia, a common risk factor for vascular disease, stroke and possibly neurodegenerative diseases [2].
• For this purpose, we mated a hyperhomocysteinemic CBS(tm1Unc) mouse carrying a heterozygous dominant mutation in cystathionine-beta-synthase (CBS*) with the APP*/PS1* mouse model of brain amyloidosis [3].
• The transgenic Cbs-/- animals exhibit facial alopecia, have moderate liver steatosis and are slightly smaller than heterozygous littermates [4].
• Cystathionine beta synthase deficiency promotes oxidative stress, fibrosis, and steatosis in mice liver [5].

High impact information on Cbs

• Hence, mild hyperhomocysteinemia due to reduced CBS expression impairs endothelium-dependent vasodilation, likely due to impaired nitric oxide bioactivity, and increased oxidative stress apparently contributes to inactivating nitric oxide in chronic, mild hyperhomocysteinemia [6].
• CBS(-/+) mice demonstrated impaired acetylcholine-induced aortic relaxation and a paradoxical vasoconstriction of mesenteric microvessels in response to superfusion of methacholine and bradykinin [6].
• Plasma levels of 8-epi-PGF(2alpha) (8-IP) were somewhat increased in CBS(-/+) mice, but liver levels of 8-IP and phospholipid hydroperoxides, another marker of oxidative stress, were normal [6].
• Aortic tissue from CBS(-/+) mice also demonstrated greater superoxide production and greater immunostaining for 3-nitrotyrosine, particularly on the endothelial surface [6].
• The absence of caspase-3 activation, DNA fragmentation, and TUNEL-positive cells shows that protective signals may counteract apoptotic signals in liver of CBS-deficient mice [5].

Chemical compound and disease context of Cbs

• Hyperhomocysteinemia (HHCY) is a consequence of impaired methionine/cysteine metabolism and is caused by deficiency of vitamins and/or enzymes such as cystathionine beta-synthase (CBS) [7].
• Folate dependence of hyperhomocysteinemia and vascular dysfunction in cystathionine beta-synthase-deficient mice [8].
• Mice heterozygous for a targeted disruption of the cystathionine beta-synthase gene (Cbs(+/-)) and wild-type littermates (Cbs(+/+)) were fed either a control diet or a high methionine/low folate (HM/LF) diet for 6 to 8 months to produce graded hyperhomocysteinemia [9].

Biological context of Cbs

• The homologous locus in the mouse (Cbs) was mapped to the proximal half of mouse chromosome 17 by Southern analysis of Chinese hamster X mouse somatic cell hybrid DNA [10].
• The very close physical linkage of mouse Cbs and Crya-1, combined with data that localize homologs of the closely flanking markers H2k and Pim-1 to human chromosome 6, suggests that the human 21q22/mouse chromosome 17 conserved segment is of a very limited total physical size and is likely to contain a relatively small number of genes [11].
• Furthermore, the Cbs+/- genotype did not confer a significant disadvantage compared with the Cbs+/+ genotype in hepatocytes challenged by oxidative stress from exposure to tertiary butylhydroperoxide [12].
• To complete the previous data, we used in situ hybridization and Northern blotting to characterize the spatial and temporal patterns of Cbs gene expression during mouse development [13].
• Homozygous mutants completely lacking cystathionine beta-synthase were born at the expected frequency from matings of heterozygotes, but they suffered from severe growth retardation and a majority of them died within 5 weeks after birth [14].

Anatomical context of Cbs

• Homologous recombination in mouse embryonic stem cells was used to inactivate the cystathionine beta-synthase [L-serine hydrolyase (adding homocysteine), EC 4.2.1.22] gene [14].
• Immunohistochemical analyses showed that the CBS protein was localized in most areas of the brain but predominantly in the cell bodies and neuronal processes of Purkinje cells and Ammon's horn neurons [13].
• Histological and histomorphometric analyses revealed that CBS-deficient mice have wrinkled skin with hyperkeratinosis of the epidermis and thinning of the dermis [15].
• Cystathionine beta-synthase, a key enzyme for homocysteine metabolism, is preferentially expressed in the radial glia/astrocyte lineage of developing mouse CNS [16].
• Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid [17].

Associations of Cbs with chemical compounds

• We have generated double knock-out mice with targeted deletions of the genes for apolipoprotein E (apoE) and cystathionine beta-synthase (CBS), which converts Hcy to cystathionine [1].
• MMP-9 was specifically induced in CBS -/+ mice and inhibited by CF treatment [18].
• Homozygous disruption of Cbs lowered cysteine concentration in all three organs [12].
• Homocysteinemia in mice is sensitive to a disruption of Cbs and to methyl donor intake [19].
• Cyclic GMP accumulation following acetylcholine treatment was also impaired in isolated aortic segments from CBS(-/+) mice, but aortic relaxation and mesenteric arteriolar dilation in response to sodium nitroprusside were similar to wild-type [6].

Regulatory relationships of Cbs

• RESULTS: Plasma total homocysteine was elevated with the high-methionine diet compared with the control diet for both Cbs+/+ (7.9+/-1.0 versus 5.0+/-0.5 micromol/L; P<0.05) and Cbs+/- (20.5+/-3.1 versus 8.2+/-0.9 micromol/L; P<0.001) mice [20].

Other interactions of Cbs

• The alpha-A-crystallin and cystathionine beta-synthase genes are physically very closely linked in proximal mouse chromosome 17 [11].
• To induce PPAR-alpha, mice were administered 8 microg/ml of ciprofibrate (CF) and grouped: 1) wild type (WT), 2) WT + CF, 3) CBS, 4) CBS + CF (n = 6 in each group) [18].
• Endogenous hydrogen sulfide (H(2)S) is naturally synthesized in various types of mammalian cells from l-cysteine in a reaction catalyzed by two enzymes, cystathionine-gamma-lyase (CSE) and/or cystathionine-beta-synthase [21].
• Commensurate with the difference in hepatic mRNA paraoxonase 1 abundance, the mean hepatic activity of paraoxonase 1, an enzyme that protects low density lipoprotein from oxidation, was 3-fold lower in homozygous CBS-deficient mice [22].
• Moreover, serum cholesterol/triglyceride distribution in lipoprotein fractions was altered in CBS(-/-) mice [7].

Analytical, diagnostic and therapeutic context of Cbs

• We used a combination of differential display and cDNA arrays to identify genes differentially expressed during hyperhomocysteinemia in brain of CBS-deficient mice [2].
• Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia [14].
• High CysAlb and Hcy levels were observed in a rat model of bowel ischemia/reperfusion while high HcyAlb and Hcy levels with no CysAlb were observed in the CBS deficient mice [23].
• Incidences of duodenal tumor induced by oral administration of hydrogen peroxide (HPO) and catalase activities in the duodenal mucosa, blood and liver were correlated in C3H/HeN, C57BL/6N, (C57BL X C3H)F1 (B6C3F1) and hypocatalasemic C3H/Cbs mice [24].
• We also did not detect resistance of plasma FV to APC in hyperhomocysteinemic mice deficient in cystathionine beta-synthase (plasma tHcy, 93 +/- 16 microM) or in human volunteers with acute hyperhomocysteinemia (plasma tHcy, 45 +/- 6 microM) [25].

References