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It has been stated that elevated homocysteine level causes endothelial dysfunction and damage. By what mechanism does this happen? Why is it the endothel where elevated homocysteine causes problems?

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Short answer: homocysteine promotes elevated levels of reactive oxygen species which interfere with signalling via nitric oxide.

There is an extensive literature on this topic: a Web of Science search using [TITLE: endotheli* AND homocysteine] produces 567 hits.

The prevailing view seems to be that homocysteine causes oxidative stress in cells because autooxidation of the sulphydryl group of homocysteine promotes the production of reactive oxygen species (ROS): superoxide, hydrogen peroxide and hydroxide radical. There is also evidence for decreased levels of glutathione (GSH) and glutathione peroxidase (GPX) (McCully, 2009). The classical pathway for dealing with ROS is conversion of the primary species,superoxide, to hydrogen peroxide (by superoxide dismutase) followed by reduction of peroxide to water by GPX using GSH as a reductant. This pathway rapidly destroys ROS and importantly avoids the generation of the damaging hydroxide radical. Reduced glutathione is regenerated at the expense of NADPH.

Endothelial cells use nitric oxide (NO) to signal to surrounding smooth muscle, resulting in vasodilation. ROS react with NO, inactivating it. There is also evidence that NO production by epithial nitric oxide synthase (eNOS) is affected, and Leung et al., 2013 present data indicating that the phosphorylation level of eNOS is reduced by homocysteine. Phosphorylation is a key regulator of eNOS activity (Mount et al., 2007).

Leung SB et al. (2013) Salidroside Improves Homocysteine-Induced Endothelial Dysfunction by Reducing Oxidative Stress. Evidence-Based Complementary and Alternative Medicine 20: Article ID 679635

McCully, KS (2009) Chemical Pathology of Homocysteine. IV. Excitotoxicity, Oxidative Stress, Endothelial Dysfunction, and Inflammation. Annals Clin. Lab. Sci. 39:219-232

Mount, PF et al. (2007) Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation. J Molec. Cell. Cardiology 42: 271-279

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