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Review
. 2019 Feb 17;20(4):867.
doi: 10.3390/ijms20040867.

The Contribution of Homocysteine Metabolism Disruption to Endothelial Dysfunction: State-of-the-Art

Ruben Esse  1 , Madalena Barroso  2 , Isabel Tavares de Almeida  3 , Rita Castro  4   5   6
Affiliations
Review

The Contribution of Homocysteine Metabolism Disruption to Endothelial Dysfunction: State-of-the-Art

Ruben Esse et al. Int J Mol Sci. .

Abstract

Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid formed during the metabolism of the essential amino acid methionine. Hcy is considered a risk factor for atherosclerosis and cardiovascular disease (CVD), but the molecular basis of these associations remains elusive. The impairment of endothelial function, a key initial event in the setting of atherosclerosis and CVD, is recurrently observed in hyperhomocysteinemia (HHcy). Various observations may explain the vascular toxicity associated with HHcy. For instance, Hcy interferes with the production of nitric oxide (NO), a gaseous master regulator of endothelial homeostasis. Moreover, Hcy deregulates the signaling pathways associated with another essential endothelial gasotransmitter: hydrogen sulfide. Hcy also mediates the loss of critical endothelial antioxidant systems and increases the intracellular concentration of reactive oxygen species (ROS) yielding oxidative stress. ROS disturb lipoprotein metabolism, contributing to the growth of atherosclerotic vascular lesions. Moreover, excess Hcy maybe be indirectly incorporated into proteins, a process referred to as protein N-homocysteinylation, inducing vascular damage. Lastly, cellular hypomethylation caused by build-up of S-adenosylhomocysteine (AdoHcy) also contributes to the molecular basis of Hcy-induced vascular toxicity, a mechanism that has merited our attention in particular. AdoHcy is the metabolic precursor of Hcy, which accumulates in the setting of HHcy and is a negative regulator of most cell methyltransferases. In this review, we examine the biosynthesis and catabolism of Hcy and critically revise recent findings linking disruption of this metabolism and endothelial dysfunction, emphasizing the impact of HHcy on endothelial cell methylation status.

Keywords: S-adenosylhomocysteine; atherosclerosis; cellular methylation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Simplified diagram of methionine metabolism (adapted from [22]). Methionine is converted to S-adenosylmethionine (AdoMet) by ATP-L-methionine S-adenosyltransferase. AdoMet, serves as methyl group donor for methylation of DNA, proteins, and other biomolecules, generating S-adenosylhomocysteine (AdoHcy), which is hydrolyzed to homocysteine (Hcy) and adenosine. This hydrolysis is reversible, and AdoHcy synthesis is favored rather than its hydrolysis. Nevertheless, under normal conditions, Hcy will be rapidly removed ensuring the hydrolytic direction. The biochemical removal of Hcy is either through the transsulfuration pathway, whose rate-limiting step is catalyzed by cystathionine β-synthase (CBS), or by its remethylation to methionine. This remethylation can be folate-dependent (requiring the enzymatic activities of methionine synthase (MS) and 5,10-methylenetetrahydrofolate reductase (MTHFR)) or folate-independent (requiring the enzymatic activity of betaine-homocysteine methyltransferase (BHMT)).
Figure 2
Figure 2
Schematic representation of the leading mechanisms proposed to underlie the implication of Hcy elevation in endothelial dysfunction and CVD: (i) impaired vasodilation, due to decreased NO bioavailability and increased vasoconstrictor molecules, as ET-1 and thromboxane; (ii) oxidative stress, either due to impaired antioxidant systems, uncoupled eNOS, and/or increased H2S. Hcy-induced ROS formation can contribute to LDL oxidation as well as to the activation of the endothelium; (iii) via upregulation of adhesion molecules and pro-inflammatory cytokines. Both ROS and H2S are known activators of the NF-κB complex, which induces the expression of various pro-inflammatory genes; and (iv) the impaired methylation reactions and increased N-homocysteinylation can further contribute to impaired protein expression/stability and/or activity. This figure was created using BioRender. ADMA: asymmetric dimethylarginine; ET-1: endothelin-1; HC: N-homocysteinylation; Me: methylation; NO: nitric oxide; oxLDL: oxidized low-density lipoprotein; ROS: reactive oxygen species.
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