Hyperhomocysteinemia and Oxidative Stress

Jacobsen, Donald W.

doi:10.1161/01.atv.20.5.1182

Cited by 150 publications

(101 citation statements)

References 44 publications

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“…Because the highly reactive thiol group of homocysteine is readily oxidized in plasma to form reactive oxygen species, it has been suggested that homocysteine exerts its cytotoxic effect through a mechanism involving oxidative damage (15-17, 48, 49). 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).…”

Section: Figurementioning

confidence: 99%

“…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). An additional hypothesis is that cellular dysfunction is caused by elevation of intracellular concentrations of homocysteine itself and that elevated plasma total homocysteine is a marker of increased intracellular homocysteine.…”

Section: Figurementioning

confidence: 99%

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

et al. 2001

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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

et al. 2001

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“…However, this hypothesis fails to explain why cysteine, which is present in plasma at much higher concentrations than homocysteine and is readily auto-oxidized, does not cause endothelial cell injury and is not considered a risk factor for cardiovascular disease. 63 Recent studies have also demonstrated that homocysteine is largely involved in antioxidant and reductive cellular biochemistry. 64 In fact, the homocysteine-dependent transsulfuration pathway is critical in the maintenance of the intracellular glutathione pools, and the regulation of this pathway is sensitive to oxidative stress conditions.…”

Section: Oxidative Stressmentioning

confidence: 99%

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

2004

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Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease, including ischemic heart disease, stroke, and peripheral vascular disease. Mutations in the enzymes responsible for homocysteine metabolism, particularly cystathionine b-synthase (CBS) or 5,10-methylenetetrahydrofolate reductase (MTHFR), result in severe forms of HHcy. Additionally, nutritional deficiencies in B vitamin cofactors required for homocysteine metabolism, including folic acid, vitamin B6 (pyridoxal phosphate), and/or B12 (methylcobalamin), can induce HHcy. Studies using animal models of genetic-and diet-induced HHcy have recently demonstrated a causal relationship between HHcy, endothelial dysfunction, and accelerated atherosclerosis. Dietary enrichment in B vitamins attenuates these adverse effects of HHcy. Although oxidative stress and activation of proinflammatory factors have been proposed to explain the atherogenic effects of HHcy, recent in vitro and in vivo studies demonstrate that HHcy induces endoplasmic reticulum (ER) stress, leading to activation of the unfolded protein response (UPR). This review summarizes the current role of HHcy in endothelial dysfunction and explores the cellular mechanisms, including ER stress, that contribute to atherothrombosis.

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“…33 Homocysteine is thought to promote the generation of ROS via the auto-oxidation of the sulfhydryl group 31 or by decreasing the intracellular levels of glutathione and glutathione peroxidase that are involved in the elimination of free radicals. 32,34,35 Enhanced levels of ROS can interfere with NO and reduce the release of NO in response to increases in flow and agonists in HHcy. Indeed, recent studies showed that in humans after methionine loading, impaired brachial artery dilations in response to acetylcholine and to the release of forearm occlusion are restored with the antioxidant ascorbic acid.…”

Section: February 2001mentioning

confidence: 99%

Flow-Induced Constriction in Arterioles of Hyperhomocysteinemic Rats Is Due to Impaired Nitric Oxide and Enhanced Thromboxane A ₂ Mediation

Bagi

Ungvári

Szollár

et al. 2001

ATVB

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Abstract-Hyperhomocysteinemia (HHcy) is thought to promote arteriosclerosis and peripheral arterial disease, in part by impairing the function of endothelium. Because flow-induced dilation is mediated by the endothelium, we hypothesized that HHcy alters this response by interfering with the synthesis/action of NO and prostaglandins. Thus, changes in the diameter of isolated, pressurized (at 80 mm Hg) gracilis skeletal muscle arterioles (diameter Ϸ170 m) from control and methionine diet-induced HHcy rats were investigated with videomicroscopy. Increases in intraluminal flow (from 0 to 25 L/min) resulted in dilations of control arterioles (maximum, 34Ϯ4 m). In contrast, increases in flow elicited constrictions of HHcy arterioles (Ϫ36Ϯ3 m). In control arterioles, the NO synthase inhibitor N -nitro-L-argininemethyl ester significantly attenuated (Ϸ50%) dilation, whereas the additional administration of indomethacin, an inhibitor of cyclooxygenase, eliminated flow-induced dilation. In the arterioles of HHcy rats, flow-induced constriction was not affected by N -nitro-L-arginine-methyl ester, whereas it was abolished by indomethacin or the prostaglandin H 2 /thromboxane A 2 (TXA 2 ) receptor antagonist SQ 29,548 or the TXA 2 synthase inhibitor CGS 13,080. Thus, in HHcy, increases in intraluminal flow elicit constrictions of skeletal muscle arterioles due to the impaired NO and enhanced TXA 2 mediation of the response, alterations that likely contribute to the development of peripheral arterial disease. Key Words: homocysteine Ⅲ arteriole Ⅲ flow-induced response Ⅲ endothelium Ⅲ nitric oxide Ⅲ thromboxane A 2 I ncreasing epidemiological and experimental evidence suggests that an elevated plasma level of homocysteine is associated with the development of peripheral arterial disease. [1][2][3][4][5] Homocysteine is a sulfur-containing amino acid that is formed during the metabolism of the essential amino acid methionine. 4 Plasma homocysteine concentration can be increased through alterations in genetic and nutritional factors, such as various enzyme (cystathione-␤-synthase, methyltetrahydrofolate reductase) abnormalities and deficiency of vitamins (folic acid, cyanocobalamin, pyridoxal phosphate), all of which participate in the metabolism of homocysteine and methionine (for further references, see Lentz et al 4 ). Previously, several mechanisms have been suggested by which elevated homocysteine levels promote peripheral arterial disease, such as vascular smooth muscle proliferation, 6 platelet activation, 7 and endothelial injury. 7 It is likely that hyperhomocysteinemia (HHcy) impairs the vasoactive function of the endothelium of arteries and arterioles before the development of morphological changes. 8 -11 Indeed, the diminished increase in hindlimb circulation to acetylcholine in monkeys with diet-induced HHcy 8,9 suggests that the dilator capacity of small arteries and arterioles responsible for tissue vascular resistance is altered by HHcy. Also, we recently demonstrated that endothelium-dependent acetylcholine-a...

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Hyperhomocysteinemia and Oxidative Stress

Cited by 150 publications

References 44 publications

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

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

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

Flow-Induced Constriction in Arterioles of Hyperhomocysteinemic Rats Is Due to Impaired Nitric Oxide and Enhanced Thromboxane A ₂ Mediation

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Hyperhomocysteinemia and Oxidative Stress

Cited by 150 publications

References 44 publications

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

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

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

Flow-Induced Constriction in Arterioles of Hyperhomocysteinemic Rats Is Due to Impaired Nitric Oxide and Enhanced Thromboxane A 2 Mediation

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Flow-Induced Constriction in Arterioles of Hyperhomocysteinemic Rats Is Due to Impaired Nitric Oxide and Enhanced Thromboxane A ₂ Mediation