Modulation of Cystathionine β-Synthase Level Regulates Total Serum Homocysteine in Mice

Wang, Liqun; Jhee, Kwang Hwan; Xiang, Hua; DiBello, Patricia M.; Jacobsen, Donald W.; Kruger, Warren D.

doi:10.1161/01.res.0000129182.46440.4a

Cited by 93 publications

(155 citation statements)

References 37 publications

(35 reference statements)

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“…28 In contrast, elevating CBS activity by overexpression of CBS decreased plasma Hcys by 45% in transgenic mice. 29 In addition, plasma Hcys levels were significantly decreased in patients with Down syndrome, because that CBS gene is located on human Chr 21 and overexpressed because of trisomy 21 in these patients. 30 Therefore, decreased expression and activity of CBS in the kidneys of SS rats from our data are suggested to be responsible for the development of hHcys in these rats.…”

Section: Discussionmentioning

confidence: 99%

Hyperhomocysteinemia Associated With Decreased Renal Transsulfuration Activity in Dahl S Rats

Chen²,

Muh³

et al. 2006

Hypertension

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Abstract-Elevated plasma homocysteine (Hcys) has been reported to participate in the development of arterial and glomerular sclerosis in Dahl salt-sensitive hypertensive (SS) rats. The mechanism resulting in hyperhomocysteinemia in these animals remains unknown. Disposal of Hcys in the kidneys plays an important role in regulating the plasma Hcys level. We, therefore, examined the activities and expressions of the enzymes involved in the metabolism of Hcys in the kidneys of SS rats, compared with that of Brown Norway rats and SSBN13 rats, a consomic subcolony of SS rats that carries a substituted chromosome 13 from Brown Norway rats. High-performance liquid chromatography analysis demonstrated that plasma Hcys levels were significantly higher in SS rats. The conversion of S-adenosylhomocysteine into Hcys via S-adenosylhomocysteine hydrolase by renal tissue was not different among these 3 rat strains. However, the metabolic rate of Hcys into cysteine was markedly reduced in the SS rat kidneys. The mRNA and protein levels of cystathionine ␤-synthase (CBS), one of the key enzymes in the transsulfuration pathway in the kidneys, were significantly lower in SS rats. In microdissected nephron segments, CBS mRNA was shown to be mainly present in renal proximal tubules (PTs). The mRNA levels of CBS in the PTs were also significantly decreased in SS rats, accompanied by a reduced CBS activity in PTs. We conclude that hyperhomocysteinemia is associated with a decreased activity and expression of CBS in renal PTs because of the defect of chromosome 13 in SS rats. (Hypertension. 2006; 47:1094-1100.)

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Section: Discussionmentioning

confidence: 99%

Hyperhomocysteinemia Associated With Decreased Renal Transsulfuration Activity in Dahl S Rats

Chen²,

Muh³

et al. 2006

Hypertension

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“…The resultant adult human CBS transgenic Cbs Ϫ/Ϫ mice had moderate hyperhomocysteinemia (plasma tHcy levels of 25 to 90 mol/L). 45 When excess zinc was removed from the diet after weaning, these mice developed extremely high levels of plasma tHcy (up to 231 mol/L) with no apparent decrement in survival. 45 The same group has generated another human CBS transgenic mouse line with a missense mutation (I278T) in the human CBS transgene corresponding to a common mutation in human CBSdeficient subjects.…”

Section: Dayal and Lentzmentioning

confidence: 99%

“…Moderate hyperhomocysteinemia (plasma tHcy levels of 18 to 60 mol/L) can be achieved by increasing the total methionine content up to 12 to 20 g/Kg 37,38 or by adding 0.5% L-methionine to the drinking water (Table 1). 39 -44 Severe hyperhomocysteinemia (plasma tHcy levels greater than 200 mol/L) can be obtained by increasing the total methionine content even higher (Table 1), 44,45 but a dietary content of methionine greater than 20 g/Kg may produce untoward effects on growth and other toxic effects. In a study of apolipoprotein E-deficient (Apoe Ϫ/Ϫ ) mice, a dietary methionine content of 22 g/Kg resulted in weight loss and a dietary methionine content of 44 g/Kg was found to cause severe growth retardation and early death.…”

Section: High-methionine Dietsmentioning

confidence: 99%

Murine Models of Hyperhomocysteinemia and Their Vascular Phenotypes

Dayal

Lentz

2008

ATVB

103

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Hyperhomocysteinemia is an established risk factor for arterial as well as venous thromboembolism. Individuals with severe hyperhomocysteinemia caused by inherited genetic defects in homocysteine metabolism have an extremely high incidence of vascular thrombosis unless they are treated aggressively with homocysteine-lowering therapy. The clinical value of homocysteine-lowering therapy in individuals with moderate hyperhomocysteinemia, which is very common in populations at risk for vascular disease, is more controversial. Considerable progress in our understanding of the molecular mechanisms underlying the association between hyperhomocysteinemia and vascular thrombotic events has been provided by the development of a variety of murine models. Because levels of homocysteine are regulated by both the methionine and folate cycles, hyperhomocysteinemia can be induced in mice through both genetic and dietary manipulations. Mice deficient in the cystathionine β -synthase (CBS) gene have been exploited widely in many studies investigating the vascular pathophysiology of hyperhomocysteinemia. In this article, we review the established murine models, including the CBS-deficient mouse as well as several newer murine models available for the study of hyperhomocysteinemia. We also summarize the major vascular phenotypes observed in these murine models.

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“…In both Down syndrome children and the CBS transgenic mice, a significant decrease in plasma homocysteine levels was observed with the overexpression of CBS [20][21][22][23][24]. In contrast, both the patients with inherited homocystinuria caused by CBS deficiency and the Cbs knockout mice had significantly elevated plasma homocysteine levels [9,[25][26][27][28][29][30].…”

Section: Discussionmentioning

confidence: 99%

A functional variant in the cystathionine β-synthase gene promoter significantly reduces congenital heart disease susceptibility in a Han Chinese population

et al. 2012

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Homocysteine is an independent risk factor for various cardiovascular diseases. There are two ways to remove homocysteine from embryonic cardiac cells: remethylation to form methionine or transsulfuration to form cysteine. Cystathionine β-synthase (CBS) catalyzes the first step of homocysteine transsulfuration as a rate-limiting enzyme. In this study, we identified a functional variant −4673C>G (rs2850144) in the CBS gene promoter region that significantly reduces the susceptibility to congenital heart disease (CHD) in a Han Chinese population consisting of 2 340 CHD patients and 2 270 controls. Individuals carrying the heterozygous CG and homozygous GG genotypes had a 15% (odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.75-0.96, P = 0.011) and 40% (OR = 0.60, 95% CI = 0.49-0.73, P = 1.78 × 10 −7 ) reduced risk to develop CHD than the wild-type CC genotype carriers in the combined samples, respectively. Additional stratified analyses demonstrated that CBS −4673C>G is significantly related to septation defects and conotruncal defects. In vivo detection of CBS mRNA levels in human cardiac tissues and in vitro luciferase assays consistently showed that the minor G allele significantly increased CBS transcription. A functional analysis revealed that both the attenuated transcription suppressor SP1 binding affinity and the CBS promoter hypomethylation specifically linked with the minor G allele contributed to the remarkably upregulated CBS expression. Consequently, the carriers with genetically increased CBS expression would benefit from the protection due to the low homocysteine levels maintained by CBS in certain cells during the critical heart development stages. These results shed light on unexpected role of CBS and highlight the importance of homocysteine removal in cardiac development.

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Modulation of Cystathionine β-Synthase Level Regulates Total Serum Homocysteine in Mice

Cited by 93 publications

References 37 publications

Hyperhomocysteinemia Associated With Decreased Renal Transsulfuration Activity in Dahl S Rats

Hyperhomocysteinemia Associated With Decreased Renal Transsulfuration Activity in Dahl S Rats

Murine Models of Hyperhomocysteinemia and Their Vascular Phenotypes

A functional variant in the cystathionine β-synthase gene promoter significantly reduces congenital heart disease susceptibility in a Han Chinese population

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