Skip to main content

Advertisement

SpringerLink
Log in

Hyperhomocysteinemia and cardiovascular disease in animal model

  • Review Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease and is associated with primary causes of mortality and morbidity throughout the world. Several studies have been carried out to evaluate the effects of a diet inducing cystathionine-β-synthase, methyltetrafolate, folic acid, and vitamin B supplemented with methionine on the homocysteine metabolism and in lowering the plasma total homocysteine levels. A large number of molecular and biomedical studies in numerous animals, such as mice, rabbits, and pigs, have sought to elevate the plasma total homocysteine levels and to identify a disease model for human hyperhomocysteinemia. However, a specific animal model is not suitable for hyperhomocysteinemia in terms of all aspects of cardiovascular disease. In this review article, the experimental progress of animal models with plasma total homocysteine levels is examined to identify a feasible animal model of hyperhomocysteinemia for different aspects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

HC:

Homocysteine

CVD:

Cardiovascular disease

ATP:

Adenosine triphosphate

MTHFR:

Methylenetetrahydrofolate reductase

CBS:

Cystathionine-β-synthase

THF:

Tetrahydrofolate

NO:

Nitric oxide

O2 :

Oxygen

SAM:

Sulfur adenosylmethionine

SAH:

S-Adenosylhomocysteine

MAT:

Methionine adenosyltransferase

MT:

Methyltransferase

MS:

Methionine synthase

References

  • Ables GP, Ouattara A, Hampton TG, Cooke D, Perodin F, Augie I, Orentreich DS (2015) Dietary methionine restriction in mice elicits an adaptive cardiovascular response to hyperhomocysteinemia. Sci Rep 5:8886. doi:10.1038/srep08886

    Article  PubMed  PubMed Central  Google Scholar 

  • Ambrosi P, Rolland PH, Bodard H, Barlatier A, Charpiot P, Guisgand G, Friggi A, Ghiringhelli O, Habib G, Bouvenot G, Garçon D, Luccioni R (1999) Effects of folate supplementation in hyperhomocysteinemic pigs. J Am Coll Cardiol 34(1):274–279

    Article  CAS  PubMed  Google Scholar 

  • Buja LM, Kita T, Goldstein JL, Watanabe Y, Brown MS (1983) Cellular pathology of progressive atherosclerosis in the WHHL rabbit. An animal model of familial hypercholesterolemia. Arteriosclerosis 3(1):87–101

    Article  CAS  PubMed  Google Scholar 

  • Catena C, Colussi G, Nait F, Capobianco F, Sechi LA (2014) Elevated homocysteine levels are associated with the metabolic syndrome and cardiovascular events in hypertensive patients. Am J Hypertens 28(7):943–950. doi:10.1093/ajh/hpu248

    Article  PubMed  Google Scholar 

  • Catena C, Colussi G, Url-Michitsch M, Nait F, Sechi LA (2015) Subclinical carotid artery disease and plasma homocysteine levels in patients with hypertension. J Am Soc Hypertens 9(3):167–175. doi:10.1016/j.jash.2014.12.020

    Article  CAS  PubMed  Google Scholar 

  • Chang L, Geng B, Yu F, Zhao J, Jiang H, Du J, Tang C (2008) Hydrogen sulfide inhibits myocardial injury induced by homocysteine in rats. Amino Acids 34(4):573–585. doi:10.1007/s00726-007-0011-8

    Article  CAS  PubMed  Google Scholar 

  • Chen Z, Karaplis AC, Ackerman SL, Pogribny IP, Melnyk S, Lussier-Cacan S, Chen MF, Pai AJ, Smith RS, Ohn SW, Bottiglieri T, Bagley P, Selhub J, Rudnicki MA, James SJ, Rozen R (2001) Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet 10:433–443

    Article  CAS  PubMed  Google Scholar 

  • Clarke R, Lewington S, Lonn E, Armitage J, Manson JAE, Bønaa KH, Spence JD, Nygård O, Jamison R, Gaziano JM, Guarino P, Bennett D, Mir F, Peto R, Collins R (2010) Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med 170:1622–1631. doi:10.1001/archinternmed.2010.348

    Article  CAS  PubMed  Google Scholar 

  • Clarke R, Bennett DA, Parish S, Verhoef P, Dotsch-Klerk M, Lathrop M, Xu P, Nordestgaard BG, Holm H, Hopewell JC, Saleheen D, Tanaka T, Anand SS, Chambers JC, Kleber ME, Ouwehand WH, Yamada Y, Elbers C, Peters B, Stewart AF, Reilly MM, Thorand B, Yusuf S, Engert JC, Assimes TL, Kooner J, Danesh J, Watkins H, Samani NJ, Collins R, Peto R, Group MSC (2012) Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS Med 9(2):e1001177. doi:10.1371/journal.pmed.1001177

    Article  PubMed  PubMed Central  Google Scholar 

  • Cohen MV, Yang XM, Liu Y, Snell KS, Downey JM (1994) A new animal model of controlled coronary artery occlusion in conscious rabbits. Cardiovasc Res 28:61–65

    Article  CAS  PubMed  Google Scholar 

  • Cottington EM (2002) Adverse event associated with methionine loading test: a case report. Arterioscler Thromb Vasc Biol 22(6):1046–1050. doi:10.1161/01.atv.0000020400.25088.a7

    Article  CAS  PubMed  Google Scholar 

  • David S, Wald ML, Morris Joan K (2002) Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 325:1202. doi:10.1136/bmj.325.7374.1202

    Article  Google Scholar 

  • Dayal S, Bottiglieri T, Arning E, Nobuyo M, Malinow MR, Sigmund CD, Heistad DD, Faraci FM, Lentz SR (2001) Endothelial dysfunction and elevation of S-adenosylhomocysteine in cystathionine β-synthase–deficient mice. Circ Res 88(11):1203–1209

    Article  CAS  PubMed  Google Scholar 

  • Dayal S, Wilson KM, Leo L, Arning E, Bottiglieri T, Lentz SR (2006) Enhanced susceptibility to arterial thrombosis in a murine model of hyperhomocysteinemia. Blood 108(7):2237–2243. doi:10.1182/blood-2006-02-005991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Devlin AM, Arning E, Bottiglieri T, Faraci FM, Rozen R, Lentz SR (2004) Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice. Blood 103:2624–2629. doi:10.1182/blood2003-09-3078

    Article  CAS  PubMed  Google Scholar 

  • Elmore CL, Matthews RG (2007) The many flavors of hyperhomocyst(e)inemia: insights from transgenic and inhibitor-based mouse models of disrupted one-carbon metabolism. Antioxid Redox Signal 9(11):1911–1922. doi:10.1089/ars.2007.1795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elnakish MT, Hassanain HH, Janssen PML (2012) Vascular Remodeling-associated hypertension leads to left ventricular hypertrophy and contractile dysfunction in profilin-1 transgenic mice. J Cardiovasc Pharmacol 60(6):544–552

    Article  CAS  PubMed  Google Scholar 

  • Elshorbagy AK, Valdivia-Garcia M, Refsum H, Smith AD, Mattocks DA, Perrone CE (2010) Sulfur amino acids in methionine-restricted rats: hyperhomocysteinemia. Nutrition 26(11–12):1201–1204. doi:10.1016/j.nut.2009.09.017

    Article  CAS  PubMed  Google Scholar 

  • Global status report on noncommunicable diseases (2014) Chapter 1 Global target 1: a 25% relative reduction in overall mortality from cardiovascular diseases, cancer, diabetes or chronic respiratory diseases. ​http://www.who.int/nmh/publications/ncd-status-report-2014/en/. Accessed 7 July 2017

  • Glowacki R, Bald E, Jakubowski H (2010) Identification and origin of Nepsilon-homocysteinyl-lysine isopeptide in humans and mice. Amino Acids 39(5):1563–1569. doi:10.1007/s00726-010-0627-y

    Article  CAS  PubMed  Google Scholar 

  • Gospe SMJ, Gietzen DW, Summers PJ, Lunetta JM, Miller JW, Selhub J, Ellis WG, Clifford AJ (1995) Behavioral and neurochemical changes in folate-deficient mice. Physiol Behav 58(5):935–941

    Article  CAS  PubMed  Google Scholar 

  • Hofmann MA, Lalla E, Lu Y, Gleason MR, Wolf BM, Tanji N, Ferran LJ Jr, Kohl B, Rao V, Kisiel W, Stern DM, Schmidt AM (2001) Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest 107:675–683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Homocysteine Lowering Trialists’ Collaboration (1998) Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ 316:894–898

    Article  Google Scholar 

  • Homocysteine Studies Collaboration (2002) Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 288:2015–2022. doi:10.1001/jama.288.16.2015

    Article  Google Scholar 

  • Humphrey LL, Fu R, Rogers K, Freeman M, Helfand M (2008) Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis. Mayo Clin Proc 83(11):1203–1212. doi:10.4065/83.11.1203

    Article  PubMed  Google Scholar 

  • Jones RWA, Jeremy JY, Koupparis A, Persad R, Shukla N (2005) Cavernosal dysfunction in a rabbit model of hyperhomocysteinaemia. BJU Int 95(1):125–130. doi:10.1111/j.1464-410X.2005.05263.x

    Article  PubMed  Google Scholar 

  • Kakimoto T, Otsuka A, Kawaguchi H, Ogata K, Tanimoto A, Kanouchi H (2014) Plasma homocysteine concentrations in novel microminipigs. In Vivo 28:579–582

    CAS  PubMed  Google Scholar 

  • Kamat PK, Kyles P, Kalani A, Tyagi N (2016) Hydrogen sulfide ameliorates homocysteine-induced alzheimer’s disease-like pathology, blood-brain barrier disruption, and synaptic disorder. Mol Neurobiol 53(4):2451–2467. doi:10.1007/s12035-015-9212-4

    Article  CAS  PubMed  Google Scholar 

  • Kang SS, Wong PWK, Malinow MR (1992) Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr 12:279–298. doi:10.1146/annurev.nu.12.070192.001431

    Article  CAS  PubMed  Google Scholar 

  • Katko M, Zavaczki E, Jeney V, Paragh G, Balla J, Varga Z (2012) Homocysteine metabolism in peripheral blood mononuclear cells: evidence for cystathionine beta-synthase activity in resting state. Amino Acids 43(1):317–326. doi:10.1007/s00726-011-1080-2

    Article  CAS  PubMed  Google Scholar 

  • Kawaguchi H, Miyoshi N, Miura N, Fujiki M, Horiuchi M, Izumi Y, Miyajima H, Nagata R, Misumi K, Takeuchi T, Tanimoto A, Yoshida H (2011) Microminipig, a non-rodent experimental animal optimized for life science research: novel atherosclerosis model induced by high fat and cholesterol diet. J Pharmacol Sci 115(2):115–121. doi:10.1254/jphs.10R17FM

    Article  CAS  PubMed  Google Scholar 

  • Klerk MVP, Clarke R, Blom HJ, Kok FJ et al (2002) MTHFR 677C->T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 288:2023–2031

    Article  CAS  PubMed  Google Scholar 

  • Lang D, Kredan MB, Moat SJ, Hussain SA, Powell CA, Bellamy MF, Powers HJ, Lewis MJ (2000) Homocysteine-induced inhibition of endothelium-dependent relaxation in rabbit aorta: role for superoxide anions. Arterioscler Thromb Vasc Biol 20:422–427

    Article  CAS  PubMed  Google Scholar 

  • Lentz SR, Piegors DJ, Fernandez JA, Erger RA, Arning E, Malinow MR, Griffin JH, Bottiglieri T, Haynes WG, Heistad DD (2002) Effect of hyperhomocysteinemia on protein C activation and activity. Blood 100(6):2108–2112. doi:10.1182/blood-2002-03-0727

    Article  CAS  PubMed  Google Scholar 

  • Leong XF, Ng CY, Jaarin K (2015) Animal models in cardiovascular research: hypertension and atherosclerosis. Biomed Res Int 2015:528–757. doi:10.1155/2015/528757

    Article  Google Scholar 

  • Li Y, Huang T, Zheng Y, Muka T, Troup J, Hu FB (2016) Folic acid supplementation and the risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. J Am Heart Assoc. doi:10.1161/JAHA.116.003768

    Google Scholar 

  • Liao J, Huang W, Liu G (2017) Animal models of coronary heart disease. J Biomed Res 31(1):3–10. doi:10.7555/JBR.30.20150051

    Google Scholar 

  • Liu G, Chen S, Zhong J, Teng K, Yin Y (2017) Crosstalk between tryptophan metabolism and cardiovascular disease, mechanisms, and therapeutic implications. Oxid Med Cell Longev 2017:1602074. doi:10.1155/2017/1602074

    PubMed  PubMed Central  Google Scholar 

  • Marcus J, Menon V (2007) Homocysteine lowering and cardiovascular disease risk: lost in translation. Can J Cardiol 23(9):707–710. doi:10.1016/S0828-282X(07)70814-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miyoshi N, Horiuchi M, Inokuchi Y, Miyamoto Y, Miura N, Tokunaga S, Fujiki M, Izumi Y, Miyajima H, Nagata R, Misumi K, Takeuchi T, Tanimoto A, Yasuda N, Yoshida H, Kawaguchi H (2010) Novel microminipig model of atherosclerosis by high fat and high cholesterol diet, established in Japan. In Vivo 24:671–680

    CAS  PubMed  Google Scholar 

  • Nandi SS, Mishra PK (2017) H2S and homocysteine control a novel feedback regulation of cystathionine beta synthase and cystathionine gamma lyase in cardiomyocytes. Sci Rep 7(1):3639. doi:10.1038/s41598-017-03776-9

    Article  PubMed  PubMed Central  Google Scholar 

  • Recchia FA, Lionetti V (2007) Animal models of dilated cardiomyopathy for translational research. Vet Res Commun 31(Suppl 1):35–41. doi:10.1007/s11259-007-0005-8

    Article  PubMed  Google Scholar 

  • Robert K, Nehmé J, Bourdon E, Pivert G, Friguet B, Delcayre C, Delabar JM, Janel N (2005) Cystathionine β synthase deficiency promotes oxidative stress, fibrosis, and steatosis in mice liver. Gastroenterology 128(5):1405–1415. doi:10.1053/j.gastro.2005.02.034

    Article  CAS  PubMed  Google Scholar 

  • Schwahn BC, Laryea MD, Chen Z, Melnyk S, Pogribny I, Garrow T, James SJ, Rozen R (2004) Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency. Biochem J 382:831–840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Selhub J (1999) Homocysteine metabolism. Annu Rev Nutr 19:217–246. doi:10.1146/annurev.nutr.19.1.217

    Article  CAS  PubMed  Google Scholar 

  • Sipahioglu MH, Saglam E, Oymak O, Sav T, Tokgoz B, Karaca H, Utas C (2005) Effect of cyclosporine A on total homocysteine level in a rabbit model. Transpl Proc 37(5):2371–2374. doi:10.1016/j.transproceed.2005.03.053

    Article  CAS  Google Scholar 

  • Tan H, Jiang X, Yang F, Li Z, Liao D, Trial J, Magera MJ, Durante W, Yang X, Wang H (2006) Hyperhomocysteinemia inhibits post-injury reendothelialization in mice. Cardiovasc Res 69(1):253–262. doi:10.1016/j.cardiores.2005.08.016

    Article  CAS  PubMed  Google Scholar 

  • Tsang HG, Rashdan NA, Whitelaw CBA, Corcoran BM, Summers KM, MacRae VE (2016) Large animal models of cardiovascular disease. Cell Biochem Funct 34:113–132. doi:10.1002/cbf.3173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Virdis A, Iglarz M, Neves MF, Amiri F, Touyz RM, Rozen R, Schiffrin EL (2003) Effect of hyperhomocysteinemia and hypertension on endothelial function in methylenetetrahydrofolate reductase-deficient mice. Arterioscler Thromb Vasc Biol 23(8):1352–1357. doi:10.1161/01.ATV.0000083297.47245.DA

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Jhee KH, Hua X, DiBello PM, Jacobsen DW, Kruger WD (2004) Modulation of cystathionine beta-synthase level regulates total serum homocysteine in mice. Circ Res 94(10):1318–1324. doi:10.1161/01.RES.0000129182.46440.4a

    Article  CAS  PubMed  Google Scholar 

  • Watanabe M, Osada J, Aratani Y, Kluckman K, Reddick R, Malinow MR, Maeda N (1995) Mice deficient in cystathionine β-synthase: animal models for mild and severe homocyst(e)inemia. Proc Natl Acad Sci USA 92:1585–1589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Werstuck GH, Lentz SR, Dayal S, Hossain GS, Sood SK, Shi YY, Zhou J, Maeda N, Krisans SK, Malinow MR, Austin RC (2001) Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest 107:1263–1273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wierzbicki AS (2016) Homocysteine and cardiovascular disease: a review of the evidence. Diab Vasc Dis Res 4(2):143–149. doi:10.3132/dvdr.2007.033

    Article  Google Scholar 

  • Zhang S, Bai YY, Luo LM, Xiao WK, Wu HM, Ye P (2014) Association between serum homocysteine and arterial stiffness in elderly: a community-based study. J Geriatr Cardiol 11(1):32–38. doi:10.3969/j.issn.1671-5411.2014.01.007

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Ji, Møller Jan, Danielsen Carl C, Bentzon Jacob, Ravn Hanne B, Austin Richard C, Falk E (2001) Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 21:1470–1476

    Article  CAS  PubMed  Google Scholar 

  • Zidan RA, Elnegris HM (2015) Effect of homocysteine on the histological structure of femur in young male albino rats and the possible protective role of folic acid. J Histol Histopathol 2(1):16. doi:10.7243/2055-091x-2-16

    Article  Google Scholar 

Download references

Acknowledgements

This research was supported by National Natural Science Foundation of China (No. 31772642, 31672457, 31702125, 41771300), National Key Research and Development Program of China (2016YFD0500504), International Partnership Program of Chinese Academy of Sciences (161343KYSB20160008), and the Ministry of Science and Technology of the People’s Republic of China (2014BAD14B01).

Author information

Authors and Affiliations

  1. Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Changsha, 410125, Hunan, China

    Md. Abul Kalam Azad, Pan Huang, Gang Liu, Wenkai Ren, Tsegay Teklebrh, Wenxin Yan, Xihong Zhou & Yulong Yin

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Md. Abul Kalam Azad & Tsegay Teklebrh

  3. Taoyuan Agro-ecosystem Research Station, Soil Molecular Ecology Section, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, 410125, China

    Gang Liu, Wenxin Yan & Yulong Yin

  4. School of Animal and Range Sciences, Haramaya University, 251, Haramaya, Dire Dawa, Ethiopia

    Tsegay Teklebrh

  5. Animal Nutrition and Human Health Laboratory, School of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China

    Yulong Yin

Authors
  1. Md. Abul Kalam Azad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenkai Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tsegay Teklebrh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wenxin Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xihong Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yulong Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gang Liu.

Ethics declarations

Conflict of interest

The author declares that there is no potential conflict of interest regarding the publication of this article.

Ethical statements

This review article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Handling Editor: J. D. Wade.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Azad, M.A.K., Huang, P., Liu, G. et al. Hyperhomocysteinemia and cardiovascular disease in animal model. Amino Acids 50, 3–9 (2018). https://doi.org/10.1007/s00726-017-2503-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-017-2503-5

Keywords

Search

Navigation