Homocysteine metabolism in experimental models of hyperhomocysteinemia in rodents. Part 1: genetic models.
Keywords:
homocysteine, hyperhomocysteinemia, modeling, metabolism, methionine S-adenosylhomocysteine
Abstract
Modeling hyperhomocysteinemia in rodents is a common way to study the role of homocysteine in pathogenesis of various diseases (myocardial infarction, stroke, cognitive impairment, Alzheimer’s disease, kidney failure, etc.). This review focuses on biochemical aspects of homocysteine metabolism, genetic methods for modeling hyperhomocysteinemia in rats and mice, and effects of these models on metabolism of both homocysteine itself and related metabolites (methionine, cysteine, S-adenosylmethionine, S-adenosylhomocysteine).
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References
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25. Gu S.X., Sonkar V.K., Katare P.B., Kumar R., Kruger W.D., Arning E., Bottiglieri T., Lentz S.R., Dayal S. Memantine Protects From Exacerbation of Ischemic Stroke and Blood Brain Barrier Disruption in Mild But Not Severe Hyperhomocysteinemia. J. Am. Heart. Assoc. 2020; 9(4): e013368.
26. Kruger W.D., Gupta S. The effect of dietary modulation of sulfur amino acids on cystathionine β synthase-deficient mice. Ann. N. Y. Acad. Sci. 2016; 1363: 80-90.
27. Weiss N, Heydrick S, Zhang YY, Bierl C, Cap A, Loscalzo J. Cellular redox state and endothelial dysfunction in mildly hyperhomocysteinemic cystathionine β-synthase-deficient mice. Arterioscler Thromb Vasc Biol 2002;22:34–41.;
28. Baumbach G.L., C.D. Sigmund, T. Bottiglieri, S.R. Lentz, Structure of cerebral arterioles in cystathionine beta-synthase-deficient mice, Circ. Res. 2002; 91: 931–937.
29. Devlin A.M., Bottiglieri T., Domann F.E., Lentz S.R. Tissue-specific changes in H19 methylation and expression in mice with hyperhomocysteinemia. J. Biol. Chem. 2005; 280(27): 25506-11.
30. Lee H.O., Wang L., Kuo Y.M., Andrews A.J., Gupta S., Kruger W.D. S-adenosylhomocysteine hydrolase over-expression does not alter S-adenosylmethionine or S-adenosylhomocysteine levels in CBS deficient mice. Mol. Genet. Metab. Rep. 2018; 15: 15-21.
31. Xiao Y., Xia J., Cheng J., Huang H., Zhou Y., Yang X., Su X., Ke Y., Ling W. Inhibition of S-Adenosylhomocysteine Hydrolase Induces Endothelial Dysfunction via Epigenetic Regulation of p66shc-Mediated Oxidative Stress Pathway. Circulation. 2019; 139(19): 2260-77. 32. Teng Y.W., Mehedint M.G., Garrow T.A., Zeisel S.H. Deletion of betainehomocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinomas. J. Biol. Chem. 2011; 286: 36258–67.
33. Symons J.D., Zaid U.B., Athanassious C.N., Mullick A.E., Lentz S.R., Rutledge J.C. Influence of folate on arterial permeability and stiffness in the absence or presence of hyperhomocysteinemia. Arterioscler. Thromb. Vasc. Biol. 2006; 26: 814–18.
2. Круглова М.П., Иванов А.В., Введенская О.Ю., Кубатиев А.А. Гипергомоцистеинемия и хроническая болезнь почек. Патологическая физиология и экспериментальная терапия. 2018; 62(4): 195-201.
3. Пизова Н.В., Пизов Н.А. Гипергомоцистеинемия и ишемический инсульт. Медицинский совет. 2017; 10: 12-7.
4. Debreceni B., Debreceni L. The role of homocysteine-lowering B-vitamins in the primary prevention of cardiovascular disease. Cardiovasc. Ther. 2014; 32(3): 130-8.
5. Dayal S., Lentz S.R. Murine models of hyperhomocysteinemia and their vascular phenotypes. Arterioscler Thromb Vasc Biol. 2008; 28(9): 1596-605.
6. Beard R.S.Jr., Bearden S.E. Vascular complications of cystathionine β-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research. Am. J. Physiol. Heart. Circ. Physiol. 2011; 300(1): 13-26.
7. Finkelstein J.D. Methionine metabolism in mammals. J Nutr Biochem. 1990; 1(5): 228-37.
8. Prudova A., Bauman Z., Braun A., Vitvitsky V., Lu S.C., Banerjee R. S-adenosylmethionine stabilizes cystathionine beta-synthase and modulates redox capacity. Proc. Natl. Acad. Sci. USA. 2006; 103(17): 6489-94.
9. Sen U., Mishra P.K., Tyagi N., Tyagi S.C. Homocysteine to hydrogen sulfide or hypertension. Cell. Biochem. Biophys. 2010; 57(2-3): 49-58.
10. Stam F., van Guldener C., Ter Wee P.M., Jakobs C., de Meer K., Stehouwer C.D. Effect of folic acid on methionine and homocysteine metabolism in end-stage renal disease. Kidney Int. 2005 ; 67(1): 259-64.
11. Yamada K., Strahler J.R., Andrews P.C., Matthews R.G. Regulation of human methylenetetrahydrofolate reductase by phosphorylation. Proc. Natl. Acad. Sci. USA. 2005; 102(30): 10454-9.
12. Swanson D.A., Liu M.L., Baker P.J., Garrett L., Stitzel M., Wu J., Harris M., Banerjee R., Shane B., Brody L.C. Targeted disruption of the methionine synthase gene in mice. Mol. Cell. Biol. 2001; 21: 1058–65.
13. Dayal S., Devlin A.M., McCaw R.B., Liu M.L., Arning E., Bottiglieri T., Shane B., Faraci F.M., Lentz S.R. Cerebral vascular dysfunction in methionine synthase-deficient mice. Circulation. 2005; 112: 737– 44.
14. Elmore C.L., Wu X., Leclerc D., Watson E.D., Bottiglieri T., Krupenko N.I., Krupenko S.A., Cross J.C., Rozen R., Gravel R.A., Matthews R.G. Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase. Mol. Genet. Metab. 2007; 91: 85–97.
15. Chen Z., Karaplis A.C., Ackerman S.L., Pogribny I.P., Melnyk S., Lussier-Cacan S., Chen M.F., Pai A., John S.W., Smith R.S., Bottiglieri T., Bagley P., Selhub J., Rudnicki M.A., James S.J., Rozen R. Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum. Mol. Genet. 2001; 10: 433–43.
16. Jakubowski H., Perla-Kaján J., Finnell R.H., Cabrera R.M., Wang H., Gupta S., Kruger W.D., Kraus J.P., Shih D.M. Genetic or nutritional disorders in homocysteine or folate metabolism increase protein N-homocysteinylation in mice. FASEB J. 2009; 23(6): 1721-7.
17. Neves M.F., Endemann D., Amiri F., Virdis A., Pu Q., Rozen R., Schiffrin E.L. Small artery mechanics in hyperhomocysteinemic mice: effects of angiotensin II. J. Hypertens. 2004; 22: 959–66.
18. Matthews R.G, Elmore C.L. Defects in homocysteine metabolism: diversity among hyperhomocyst(e)inemias. Clin. Chem. Lab. Med. 2007; 45(12): 1700-3.
19. Mikael L.G., X.L.Wang, Q. Wu, H. Jiang, K.N. Maclean, R. Rozen, Hyperhomocysteinemia is associated with hypertriglyceridemia inmice with methylenetetrahydrofolate reductase deficiency, Mol. Genet. Metab. 2009; 98: 187–94.
20. Devlin A.M., Arning E., Bottiglieri T., Faraci F.M., Rozen R., Lentz S.R. Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice. Blood. 2004; 103: 2624–9.
21. Akahoshi N., Yokoyama A., Nagata T., Miura A., Kamata S., Ishii I. Abnormal Amino Acid Profiles of Blood and Cerebrospinal Fluid from Cystathionine β-Synthase-Deficient Mice, an Animal Model of Homocystinuria. Biol Pharm Bull. 2019; 42(6): 1054-7.
22. Jiang X., Yang F., Tan H., Liao D., Bryan R.M., Jr. Randhawa J.K., Rumbaut R.E., Durante W., Schafer A.I., Yang X., Wang H. Hyperhomocystinemia impairs endothelial function and eNOS activity via PKC activation. Arterioscler. Thromb. Vasc. Biol. 2005; 25: 2515–21.
23. Wang L., Jhee K.H., Hua X., DiBello P.M., Jacobsen D.W., Kruger W.D. Modulation of cystathionine β- synthase level regulates total serum homocysteine in mice. Circ. Res. 2004; 94: 1318–24.
24. Gupta S., Kühnisch J., Mustafa A., Lhotak S., Schlachterman A., Slifker M.J., Klein-Szanto A., High K.A., Austin R.C., Kruger W.D. Mouse models of cystathionine β-synthase deficiency reveal significant threshold effects of hyperhomocysteinemia. FASEB J. 2009; 23: 883–93.
25. Gu S.X., Sonkar V.K., Katare P.B., Kumar R., Kruger W.D., Arning E., Bottiglieri T., Lentz S.R., Dayal S. Memantine Protects From Exacerbation of Ischemic Stroke and Blood Brain Barrier Disruption in Mild But Not Severe Hyperhomocysteinemia. J. Am. Heart. Assoc. 2020; 9(4): e013368.
26. Kruger W.D., Gupta S. The effect of dietary modulation of sulfur amino acids on cystathionine β synthase-deficient mice. Ann. N. Y. Acad. Sci. 2016; 1363: 80-90.
27. Weiss N, Heydrick S, Zhang YY, Bierl C, Cap A, Loscalzo J. Cellular redox state and endothelial dysfunction in mildly hyperhomocysteinemic cystathionine β-synthase-deficient mice. Arterioscler Thromb Vasc Biol 2002;22:34–41.;
28. Baumbach G.L., C.D. Sigmund, T. Bottiglieri, S.R. Lentz, Structure of cerebral arterioles in cystathionine beta-synthase-deficient mice, Circ. Res. 2002; 91: 931–937.
29. Devlin A.M., Bottiglieri T., Domann F.E., Lentz S.R. Tissue-specific changes in H19 methylation and expression in mice with hyperhomocysteinemia. J. Biol. Chem. 2005; 280(27): 25506-11.
30. Lee H.O., Wang L., Kuo Y.M., Andrews A.J., Gupta S., Kruger W.D. S-adenosylhomocysteine hydrolase over-expression does not alter S-adenosylmethionine or S-adenosylhomocysteine levels in CBS deficient mice. Mol. Genet. Metab. Rep. 2018; 15: 15-21.
31. Xiao Y., Xia J., Cheng J., Huang H., Zhou Y., Yang X., Su X., Ke Y., Ling W. Inhibition of S-Adenosylhomocysteine Hydrolase Induces Endothelial Dysfunction via Epigenetic Regulation of p66shc-Mediated Oxidative Stress Pathway. Circulation. 2019; 139(19): 2260-77. 32. Teng Y.W., Mehedint M.G., Garrow T.A., Zeisel S.H. Deletion of betainehomocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinomas. J. Biol. Chem. 2011; 286: 36258–67.
33. Symons J.D., Zaid U.B., Athanassious C.N., Mullick A.E., Lentz S.R., Rutledge J.C. Influence of folate on arterial permeability and stiffness in the absence or presence of hyperhomocysteinemia. Arterioscler. Thromb. Vasc. Biol. 2006; 26: 814–18.
Published
2020-11-26
How to Cite
Ivanov A., Virus E., Loginov V., Zimina I., Burdennyy A., Alexandrin V., Kubatiev A. Homocysteine metabolism in experimental models of hyperhomocysteinemia in rodents. Part 1: genetic models. // Patologicheskaya Fiziologiya i Eksperimental’naya Terapiya (Pathological physiology and experimental therapy). 2020. VOL. 64. № 4. PP. 118–124.
Issue
Section
Reviews
