Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

“…Heterozygous CBSdeficient mice develop endothelial dysfunction by decreasing vascular nitric oxide bioavailability, thereby leading to impaired vasorelaxation. 41,46 This association is not unique to CBS-deficient mice, as endothelial dysfunction has also been observed in other animal models of HHcy, including rabbits and monkeys. 67,[110][111][112][113] Although CBS-deficient mice or non-murine models of HHcy exhibit endothelial dysfunction, there is no evidence of atherosclerotic lesion development.…”

“…37 Expression of eNOS does not appear to be decreased during HHcy, and vasodilator responses to nitroprusside or nitroglycerin are preserved, suggesting that sensitivity of vascular muscle to nitric oxide is relatively normal. 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.…”

“…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.…”

Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways

“…However, the oxidative stress hypothesis fails to explain why cysteine, which is present in plasma in concentrations 25-to 30-fold higher than those of total homocysteine and is readily oxidized, is not usually considered to be a risk factor for cardiovascular disease (20). In fact, markers of oxidative stress have not been observed in cultured human cells exposed to homocysteine (21)(22)(23)(24) or in the livers of hyperhomocysteinemic mice (49). However, given that homocysteine decreases the expression of a wide range of antioxidant enzymes (21) and impairs the activity of glutathione peroxidase (50), homocysteine may indirectly enhance oxidative damage in certain cells or tissues by decreasing cellular antioxidant potential (20,51).…”

Hyperkeratosis in cystathionine beta synthase‐deficient mice: An animal model of hyperhomocysteinemia

“…These mice, which have elevated level of plasma homocysteine concentrations (Watanabe et al, 1995), also exhibit some pathological features of hyperhomocysteinemia such as endothelial dysfunctions (Eberhardt et al, 2000;Lentz et al, 2000;Dayal et al, 2001;Weiss et al, 2001Weiss et al, , 2002Denis et al, 2003).…”