Published online before print April 22, 2004, doi: 10.1161/01.RES.0000129182.46440.4a
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© 2004 American Heart Association, Inc.
Molecular Medicine |
Modulation of Cystathionine ß-Synthase Level Regulates Total Serum Homocysteine in Mice
From the Division of Population Science (L.W., K.H.J., X.H., W.D.K.), Fox Chase Cancer Center, Philadelphia, Pa; and the Department of Cell Biology (P.M.D., D.W.J.), Lerner Research Center, Cleveland Clinic Foundation, Ohio. The present address for K.H.J. is the Department of Applied Chemistry, Kumoh National Institute of Technology, Korea.
Correspondence to Warren D. Kruger, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111. E-mail warren.kruger{at}fccc.edu
Elevated total plasma homocysteine is an independent risk factor in the development of vascular disease in humans. Cystathionine ß-synthase (CBS) is an enzyme that condenses homocysteine with serine to form cystathionine. In this article, we describe the effects of modulating CBS activity using a transgenic mouse that contains the human CBS cDNA under control of the zinc-inducible metallothionein promoter (Tg-CBS). In the presence of zinc, Tg-CBS mice have a 2- to 4-fold increase in liver and kidney CBS activity compared with nontransgenic littermates. Transgenic mice on standard mouse chow had a 45% decrease in their serum homocysteine (12.1 to 7.2 µmol/L; P<0.0001) when zinc was added to drinking water, although zinc had minimal effect on their nontransgenic siblings (13.2 µmol/L versus 13.0 µmol/L; P=NS). Tg-CBS mice maintained on a high-methionine, low-folate diet also had significantly lower serum homocysteine compared with control animals (179 µmol/L versus 242 µmol/L; P<0.02). CBS overexpression also significantly lowered serum cysteinylglycine (3.6 versus 2.8 µmol/L; P<0.003) levels and reduced the levels of many amino acids in the liver. We also found that expression of Tg-CBS rescued the severe hyperhomocysteinemia and neonatal lethality of Cbs deletion animals. Our results show that elevating CBS activity is an effective method to lower plasma homocysteine levels. In addition, the creation of an inducible mouse system to modulate plasma homocysteine will also be useful in the study of homocysteine-related vascular disease.
Key Words: metabolism • genetics • amino acids • cardiovascular diseases
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