Hyperhomocysteinemia, Oxidative Stress, and Cerebral Vascular Dysfunction

Abstract

A n elevated circulating concentration of the sulfurcontaining amino acid homocysteine, hyperhomocysteinemia, produces complex changes within the blood vessel wall. In the peripheral circulation, these changes include oxidative stress, proinflammatory effects such as expression of tumor necrosis factor-␣ and inducible nitric oxide (NO) synthase (iNOS), and endothelial dysfunction. [1][2][3][4][5][6] Hyperhomocysteinemia-induced oxidative stress may occur as a result of decreased expression and/or activity of key antioxidant enzymes as well as increased enzymatic generation of superoxide anion (the precursor for multiple reactive oxygen and reactive nitrogen species). 2,4 Do hyperhomocysteinemia-induced changes occur in the cerebral circulation and why are they potentially important? Hyperhomocysteinemia is a an emerging risk factor for carotid artery disease (atherosclerosis) and stroke and is associated with Alzheimer's disease and vascular dementia. 7-11 It was not until relatively recently, however, that experimental studies began to define the impact of hyperhomocysteinemia on cerebral vascular biology and the molecular mechanisms that account for these changes. This work has been facilitated by the development of mouse models with genetic alterations in different components of the homocysteine metabolic pathway (see below).Early work in the cerebral microcirculation observed that acute local administration of a very high concentration of homocysteine (1 mmol/L) in the presence of exogenous Cu 2ϩ produced superoxide-mediated reductions in resting cerebral blood flow (CBF) as well as attenuation of endotheliumdependent and NO-mediated responses. 12 Our group was among the first to show that mild chronic hyperhomocysteinemia produces endothelial dysfunction in the carotid artery. 1,13 Moderate hyperhomocysteinemia, induced by acute methionine loading, produces impaired autoregulatory responses in older humans. 14 When considering the consequences of impairment of normal endothelial function, it is important to recall that genetic analyses have demonstrated cosegregation of endothelial dysfunction with a stroke-prone phenotype, 15 and endothelial dysfunction is emerging as an independent predictor of clinical events including stroke. 16 Levels of circulating homocysteine are determined by multiple mechanisms including genetic and dietary factors. Several genetically altered mice deficient in key enzymes within the homocysteine metabolic pathway have now been developed. 17 These include mice deficient in expression of cystathionine ␤-synthase (CBS), methylenetetrahydrofolate reductase (MTHFR), and methione synthase (MS). 17 All these genetic alterations result in hyperhomocysteinemia, the magnitude of which is dependent on the content of methionine, folate, and choline in the diet. The development of these animals, along with combined dietary interventions, now allows mechanistic studies of effects of mild to moderate hyperhomocysteinemia on the vasculature. We have used these novel genetic models in studies of ...

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

“…38 Many studies using animal models and human subjects have demonstrated that HHcy induces endothelial dysfunction. 39,40 The degree of impairment of endothelium-dependent relaxation during HHcy is similar to that of other risk factors such as hypercholesterolemia and hypertension. 39 The mechanisms by which HHcy induces endothelial dysfunction are incompletely defined.…”

“…41 It is likely, therefore, that HHcy decreases nitric oxide bioavailability through alternative mechanisms, such as accelerated oxidative inactivation of nitric oxide. 40 Homocysteine-induced oxidative inactivation of nitric oxide has been observed in vitro in cultured endothelial cells, 42 and evidence for increased oxidative inactivation of nitric oxide during HHcy has been obtained in animals using both pharmacological 41,[43][44][45][46] and genetic 47,48 approaches. Several types of reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and peroxynitrite, may contribute to the oxidative inactivation of endothelium-derived nitric oxide in HHcy.…”

“…Several types of reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and peroxynitrite, may contribute to the oxidative inactivation of endothelium-derived nitric oxide in HHcy. 40 Another potential mechanism for endothelial dysfunction during HHcy is inhibition of nitric oxide production caused by asymmetric dimethylarginine (ADMA), an endogenous eNOS Figure 1 Homocysteine metabolic pathways. Dietary methionine is converted to the methyl donor S-adenosylmethionine (SAM) and is demethylated to Sadenosylhomocysteine (SAH) and homocysteine.…”

Change in platelet endothelial cell adhesion molecule-1 immunoreactivity in the dentate gyrus in gerbils fed a folate-deficient diet

“…Control of folate has a major impact on homosysteine levels, with an inverse relationship between plasma folate and homocysteins levels [11,26]. Many epidemiological studies have related folate deficiency and resultant elevated plasma total homocysteine levels with an increased risk of vascular disease and ischemic stroke [8,11,12,19,26]. Folic acid deficiency and high homocysteine levels can be directly toxic to cultured neurons by mechanisms that involve uracil misincorporation, impaired DNA repair, and DNA damage [20,21,23].…”

Hyperhomocysteinemia and Ischemic Stroke

“…Более того, экспериментальные исследования показывают, что увеличение общего уровня ГЦ усугубляет сосудистые заболевания [47]. В исследовании Han L. с соавт.…”