Stereospecific and Redox-Sensitive Increase in Monocyte Adhesion to Endothelial Cells by Homocysteine

Abstract

Objective-Previous studies have shown that elevated homocysteine (Hcy) levels promote the development of atherosclerotic lesions in atherosclerosis-prone animal models. There is evidence that oxidant stress contributes to Hcy's deleterious effects on the vasculature. The accumulation and adhesion of monocytes to the vascular endothelium is a critical event in the development of atherosclerosis. We investigated the effects of Hcy on the interaction between human endothelial cells (EC) (EC line EA.hy 926 and primary human umbilical vein EC [HUVEC]) and the monocytic cell line THP-1, and the impact of vascular oxidant stress and redox-sensitive signaling pathways on these events. Methods and Results-L-Hcy, but not D-Hcy, increases the production of reactive oxygen species inside EC, enhances nuclear factor(NF)-B activation, and stimulates intercellular adhesion molecule-1 (ICAM-1) RNA transcription and cell surface expression. This leads to a time-and dose-dependent increase in monocyte adhesion to ECs. Pretreatment of ECs with superoxide scavengers (MnTBAP and Tiron) or with an inhibitor of NF-B activation abolished Hcy-induced monocyte adhesion, ICAM-1 expression, and nuclear translocation of NF-B. Conclusions-These findings suggest that reactive oxygen species produced under hyperhomocysteinemic conditions may induce a proinflammatory situation in the vessel wall that initiates and promotes atherosclerotic lesion development. A key event in the vascular pathobiology associated with hyperhomocysteinemia is the induction of endothelial dysfunction. 1 This can be detected by impaired endotheliumdependent vasodilator function in animal models of mild hyperhomocystinemia 2-4 and in patients with either acutely 5 or chronically 6 elevated plasma homocysteine (Hcy) levels. It indicates a reduction in bioavailable nitric oxide (NO). This is thought to be caused by increased vascular oxidant stress under hyperhomocysteinemic conditions leading to inactivation of NO 7 and/or to elevated plasma levels of the NO synthase inhibitor asymmetrical dimethylarginine leading to decreased synthesis. 8,9 Endothelial dysfunction not only impairs regulation of vasomotion but also affects the regulation of interactions of the endothelium with circulating inflammatory cells, of endothelium-dependent thrombotic and fibrinolytic mechanisms, and of cell growth within the vessel wall. 10 Recently it has been shown that exposure of cultured endothelial cells (ECs) to Hcy leads to endothelial activation resulting in increased expression of chemokines 11 and adhesion molecules. 12-14 Furthermore, increased P-selectin expression by activated EC and/or platelets has been shown in plasma and aortic sections of mildly hyperhomocysteinemic heterozygous cystathionine ␤ synthase-deficient mice. 4 Induction of hyperhomocysteinemia in apolipoprotein E-null mice enhanced the expression of receptors for advanced glycation end products, vascular cell adhesion molecule (VCAM)-1, E-selectin, tissue factor (TF), and matrix metalloproteinase (MMP)-9 in th...

Hyperhomocysteinemia, as an Independent Risk Factor for Retinal Venous Occlusion in an Indian Population

“…These include decreased bioavailability of nitric oxide [10], altered expression of various thrombotic factors, mitogenic effect on arterial smooth muscle cells [11], and expression of acute stressrelated genes [12]. Moreover, the high pK a of the sulfhydryl group (pK a = 10.0) of Hcys is responsible for the formation of stable disulfide bonds with protein cysteine residues and, in the process, alters or impairs the function of many proteins.…”

“…Clinical feature depends on the site and degree of atherosclerotic changes. The mechanisms by which Hcys damages the blood vessel wall seems to be multifactorial [9][10][11][12][13][14].…”

Variations in the Natural Course of Elevated Plasma Homocysteine Level Following Retinal Vein Occlusion at Presentation.

“…[15] Hcys is metabolised into hcysthiolactone that contributes to Hcys toxicity in humans. [16] (Hcys-thiolactone hypothesis)…”

Forebrain Ischemic Stroke and the Phenomenon of Ischemic Tolerance: Is Homocysteine Foe or Friend?

“…Interestingly, mutual tissue production of strong oxidant peroxynitrite stimulates tyrosine nitration, which leads to protein functional alterations and cellular dysfunction [26]. "uto-oxidation of Hcy metabolites results in H 2 O 2 accumulation and as shown by [ ] and later by [8] prolonged incubation of neurons with Hcy metabolites leads to necrotic cell death.…”