Interactions of hyperhomocysteinemia and T cell immunity in causation of hypertension

Abstract

Although hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases (CVD), there is a debate on whether HHcy is a risk factor or just a biomarker. Interestingly, homocysteine lowering strategies in humans had very little effect on reducing the cardiovascular risk, as compared with animals; this may suggest heterogeneity in human population and epigenetic alterations. Moreover, there are only few studies that suggest the idea that HHcy contributes to CVD in the presence of other risk factors such as inflammation, a known risk factor for CVD. Elevated levels of homocysteine have been shown to contribute to inflammation. Here, we highlight possible relationships between homocysteine, T cell immunity, and hypertension, and summarize the evidence that suggested these factors act together in increasing the risk for CVD. In light of this new evidence, we further propose that there is a need for evaluation of the causes of HHcy, defective remethylation or defective transsulfuration, which may differentially modulate hypertension progression, not just the homocysteine levels.

Keywords: T cells; cardiovascular disease; hyperhomocysteinemia; hyperhomocystéinémie; hypertension; inflammation; lymphocytes T; maladie cardiovasculaire.

Fig. 1

Major steps in homocysteine metabolism. Schematic representation of key steps in homocysteine metabolism. CBS, cystathionine β-synthase; CSE, cystathionine γ-lyase; CH₃. THF, 5-methyl tetrahydrofolate; DMG, dimethylglycine; THF, methenyltetrahydrofolate; B₁₂, vitamin B12; B₆, vitamin B6.

Fig. 2

Homocysteine mediated modulation of T cell immune response. Under physiological conditions, antigen stimulation of T cell receptor (TCR), engagement of cluster of differentiation 28 (CD28) by co-stimulatory molecules on antigen presenting cells provide the necessary signals for full activation of T cells that enter into the cell cycle. IL-2 produced by the activated T cells in autocrine fashion further influence the extent to which T cells divide. Interestingly, hyperhomocysteinemia, although it enhances the proliferation of activated T cells, does not augment IL-2 secretion by the T cells. Activation of T cells also upregulates important enzymes, cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), in the methionine (MET) cycle. Under these conditions, we propose extracellular MET or homocysteine (HCY) can feed into MET metabolism in T cells and result in the production of L-cysteine (CyS) intracellularly. Intracellular cysteine thus formed feeds in to the pathways generating H₂S and glutathione (GSH), which enhances the T cell expansion. ASC, alanine-serine-cysteine; CD25, cluster of differentiation 25; GSSG, oxidized glutathione. [Color online.]

Fig. 3

T cell immunity in hyperhomocysteinemia (HHcy)-mediated hypertension. The hypothesis is that HHcy-mediated oxidative damage in end organs (kidney, brain, and vasculature), APC (antigen presenting cells), and T cells leads to their accumulation in the end organs. Such accumulation facilitates T cell activation through interactions with APC. HHcy can promote activated T cell proliferation, which may lead to skewed T cell subpopulations and heightened inflammation. These events further cause exacerbation of end-organ damage and hypertension.