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Homocysteine as a Biomarker in Vascular Disease

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Biomarkers in Cardiovascular Disease

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Abstract

Elevated concentrations of homocysteine (Hcy) result from either mutations in the genes encoding Hcy-metabolizing enzymes or from deficiencies of their cofactors. Even a mild increase in the levels of Hcy is considered a risk factor for a number of diseases in humans, such as cardiovascular disease, stroke, neurodegenerative disorders like dementia and Alzheimer’s disease, birth defects, complicated pregnancies, and bone fractures. However, it has not yet been elucidated whether Hcy is a causative agent. Here, we present an overview of recent data on the putative mechanisms of Hcy in hyperhomocysteinemia-related vascular diseases. However, the mechanism by which Hcy can promote atherogenesis remains unclear. Endothelial dysfunction is the central condition on which a number of factors converge. Increased oxidative stress with alterations in nitric oxide, protein thiolation, and homocysteinylation, as well as Hcy-induced epigenetic changes, are involved in the pathogenesis. Although combined folic acid and B-vitamin therapy substantially reduces Hcy levels, the results are mixed from most clinical trials testing the benefit of vitamin supplementation on cardiovascular events, but they have generally failed to show a significant effect.

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Abbreviations

5-MTHF:

5-methyltetrahydrofolate

ADMA:

Asymmetric dimethylarginine

CBS:

Cystathionine β-synthase

CSE:

Cystathionine γ-lyase

eNOS:

Endothelial nitric oxide synthase

ER:

Endoplasmic reticulum

GSH:

Glutathione

Hcy:

Homocysteine

HDL:

High density lipoprotein

HHcy:

Hyperhomocysteinemia

iNOS:

Inducible nitric oxide synthase

MAT:

Methionine adenosyltransferase

MTHFR:

Methylenetetrahydrofolate reductase

MTs:

Methyltransferase

NFκB:

Nuclear factor –kappa B

NO:

Nitric oxide

NOS:

Nitric oxide synthase

ROS:

Reactive oxygen species

SAH:

S-adenosylhomocysteine

SAM:

S-adenosylmethionine

tHcy:

Total homocysteine

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Authors and Affiliations

  1. Faculty of Medicine, Department of Pediatrics, Obstetrics and Ginecology, University of Valencia, Valencia, Spain

    Pilar Codoñer-Franch

  2. Faculty of Medicine, Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain

    Eulalia Alonso-Iglesias

Authors
  1. Pilar Codoñer-Franch
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  2. Eulalia Alonso-Iglesias
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Correspondence to Pilar Codoñer-Franch .

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Editors and Affiliations

  1. Department of Biomedical Sciences, University of Westminster, London, United Kingdom

    Vinood B. Patel

  2. Sciences Division, King's College, London, United Kingdom

    Victor R. Preedy

Definitions

Endothelial dysfunction

The earliest manifestation of vascular disease. It is characterized by the incapacity of the endothelium to sustain an adequate vasodilator and antithrombotic response to physiological needs. In other words, a shift of the endothelium towards limited vasodilation, proinflammatory and prothrombotic properties.

Folate cycle

Set of cyclic reactions implicated in the conversion and recycling of folate into methyltetrahydrofolate (5-MTHF), its active form as a methyl donor.

Homocysteine levels in plasma

Refers to the levels of total circulating homocysteine that are conventionally assessed in analytical practice. It includes both free homocysteine and homocysteine bound to other metabolites or molecules through disulfide bonds.

Homocysteine

A sulfur-containing amino acid that is not provided by proteins, but is generated as an intermediary metabolite in the conversion of methionine into cysteine.

Hyperhomocysteinemia

The term is usually used to refer levels of circulating homocysteine exceeding 15 μM. This cut off value must be contextualized according to age, gender and lifestyle factors..

N-Homocysteinylation

A spontaneous non-enzymatic reaction of homocysteine thiolactone with the ε-amino group of lysine residues in proteins to form N-linked Hcy-protein adducts.

Oxidative stress

A metabolic imbalance between pro-oxidant and antioxidant species that favor oxidative damage to biological molecules and over activation of redox-sensitive pathways.

Remethylation pathway

The conversion of homocysteine back to methionine by transfer of a methyl group that, in most of the tissues, is provided by 5-methyltetrahydrofolate (5-MTHF), in a reaction that is folate- and vitamin B12-dependent.

S-Homocysteinylation

A spontaneous non-enzymatic oxidation reaction between the -SH group (thiol group) of homocysteine and the -SH group of cysteine residues in proteins to form S-S (disulfide bond)-linked Hcy-protein adducts.

Transmethylation pathway

A series of enzyme catalyzed reactions implicated in the generation of homocysteine from methionine. An intermediate in this process is S-adenosylmethionine, the main provider for methyl groups in biological reactions, such as those implicated in the epigenetic control of gene expression.

Transsulfuration pathway

A set of vitamin B6-dependent enzyme catalyzed reactions that account for the conversion of homocysteine into cysteine.

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Codoñer-Franch, P., Alonso-Iglesias, E. (2015). Homocysteine as a Biomarker in Vascular Disease. In: Patel, V., Preedy, V. (eds) Biomarkers in Cardiovascular Disease. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7741-5_11-1

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  • DOI: https://doi.org/10.1007/978-94-007-7741-5_11-1

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