Homocysteine Enhances Endothelial Apoptosis via Upregulation of Fas-Mediated Pathways

Suhara, Toshiaki; Fukuo, Keisuke; Yasuda, Osamu; Tsubakimoto, Maki; Takemura, Yukihiro; Kawamoto, Hidenobu; Yokoi, Taishi; Mogi, Masaki; Kaimoto, Taeko; Ogihara, Toshio

doi:10.1161/01.hyp.0000127914.94292.76

Cited by 80 publications

(68 citation statements)

References 59 publications

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“…Potential mechanisms whereby homocysteine might contribute to atherosclerosis include endothelial injury due to release of reactive oxygen species by oxidized homocysteine, increased oxidation of lowdensity lipoprotein, and stimulation of smooth muscle cell proliferation (31). Homocysteine enhances endothelial cell apoptosis (32). It is interesting to note that patients with SLE have increased levels of circulating apoptotic endothelial cells and reduced brachial artery flow-mediated dilation (33), and yet, despite accelerated damage, they have decreased numbers of circulating endothelial cell precursors, cells that are essential for vascular repair (34).…”

Section: Discussionmentioning

confidence: 99%

Rate and determinants of progression of atherosclerosis in systemic lupus erythematosus

Roman

Crow

Lockshin

et al. 2007

Arthritis & Rheumatism

175

127

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Objective. To determine the rate of atherosclerosis progression as well as the relationship of traditional risk factors, systemic lupus erythematosus (SLE)-related factors, and treatment to atherosis progression in SLE patients.Methods. Outpatients in the Hospital for Special Surgery SLE Registry underwent serial carotid ultrasound and clinical assessment in a longitudinal study.Results. Among 158 patients, 77 (49%) had persistent absence of atherosclerosis (carotid plaque), 36 (23%) had unchanged atherosclerosis, and 45 (28%) had progressive atherosclerosis, defined as a higher plaque score (new plaque in 25 patients and more extensive plaque in 20 patients) after a mean ؎ SD interval of 34 ؎ 9 months. Multivariate determinants of atherosclerosis progression were age at diagnosis (odds ratio [OR] 2.75, 95% confidence interval [95% CI] 1.67-4.54 per 10 years, P < 0.001), duration of SLE (OR 3.16, 95% CI 1.64-6.07 per 10 years, P < 0.001), and baseline homocysteine concentration (OR 1.24, 95% CI 1.06-1.44 per moles/liter, P ‫؍‬ 0.006). SLE patients with stable plaque and progressive plaque differed only in baseline homocysteine concentration. Atherosclerosis progression was increased across tertiles of homocysteine concentration (16.2%, 36.4%, and 56.1%; P ‫؍‬ 0.001), and homocysteine tertile was independently related to progression of atherosclerosis (OR 3.14, 95% CI 1.65-5.95 per tertile, P < 0.001). Less aggressive immunosuppressive therapy and lower average prednisone dose were associated with progression of atherosclerosis in univariate, but not multivariate, analyses. Inflammatory markers and lipids were not related to atherosclerosis progression.Conclusion. Atherosclerosis develops or progresses in a substantial minority of SLE patients during short-term followup (10% per year on average). Older age at diagnosis, longer duration of SLE, and higher homocysteine concentration are independently related to progression of atherosclerosis. These findings show that aggressive control of SLE and lowering of homocysteine concentrations are potential means to retard the development and progression of atherosclerosis in SLE.

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Section: Discussionmentioning

confidence: 99%

Rate and determinants of progression of atherosclerosis in systemic lupus erythematosus

Roman

Crow

Lockshin

et al. 2007

Arthritis & Rheumatism

175

127

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“…Elevated levels of Hcy are independent risk factor for cardiovascular diseases [Keaney et al, 1993;Suhara et al, 2004]. Because endothelial cells are lacking the cystathione beta synthase [Finkelstein, 1990[Finkelstein, , 1998], an enzyme responsible for Hcy clearance; endothelial cells are the prime target for Hcy toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…PARP; cytochrome-c; reactive oxygen species; siRNA; cardiac microvascular endothelial cells; oxidative stress; mitochondrial membrane potential; siRNA; cDNA array; TUNEL; Bax; Bcl 2 ; caspase Hyperhomocysteinemia is an independent risk factor for cardiovascular disease, stroke, and peripheral vascular disease [Jacobsen, 1998;Hankey and Eikelboom, 1999;Fallon et al, 2001;Suhara et al, 2004] [Tsai et al, 1994].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial mechanism of microvascular endothelial cells apoptosis in hyperhomocysteinemia

Tyagi

Ovechkin

Lominadze

et al. 2006

J of Cellular Biochemistry

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An elevated level of homocysteine (Hcy) limits the growth and induces apoptosis. However, the mechanism of Hcy-induced programmed cell death in endothelial cells is largely unknown. We hypothesize that Hcy induces intracellular reactive oxygen species (ROS) production that leads to the loss of transmembrane mitochondrial potential (Δψ m ) accompanied by the release of cytochrome-c from mitochondria. Cytochrome-c release contributes to caspase activation, such as caspase-9, caspase-6, and caspase-3, which results in the degradation of numerous nuclear proteins including poly (ADP-ribose) polymerase (PARP), which subsequently leads to the internucleosomal cleavage of DNA, resulting cell death. In this study, rat heart microvascular endothelial cells (MVEC) were treated with different doses of Hcy at different time intervals. Apoptosis was measured by DNA laddering and transferase-mediated dUTP nick-end labeling (TUNEL) assay. ROS production and MP were determined using florescent probes (2,7-dichlorofluorescein (DCFH-DA) and 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzamidazolocarbocyanin iodide (JC-1), respectively, by confocal microscopy. Differential gene expression for apoptosis was analyzed by cDNA array. The results showed that Hcy-mediated ROS production preceded the loss of MP, the release of cytochrome-c, and the activation of caspase-9 and -3. Moreover the Hcy treatment resulted in a decrease in Bcl 2 /Bax ratio, evaluated by mRNA levels. Caspase-9 and -3 were activated, causing cleavage of PARP, a hallmark of apoptosis and internucleosomal DNA fragmentation. The cytotoxic effect of Hcy was blocked by using small interfering RNA (siRNA)-mediated suppression of caspase-9 in MVEC. Suppressing the activation of caspase-9 inhibited the activation of caspase -3 and enhanced the cell viability and MP. Our data suggested that Hcy-mediated ROS production promotes endothelial cell death in part by disturbing MP, which results in subsequent release of cytochrome-c and activation of caspase-9 and 3, leading to cell death. KeywordsPARP; cytochrome-c; reactive oxygen species; siRNA; cardiac microvascular endothelial cells; oxidative stress; mitochondrial membrane potential; siRNA; cDNA array; TUNEL; Bax; Bcl 2 ; caspase Hyperhomocysteinemia is an independent risk factor for cardiovascular disease, stroke, and peripheral vascular disease [Jacobsen, 1998;Hankey and Eikelboom, 1999;Fallon et al., 2001;Suhara et al., 2004] [Tsai et al., 1994].Hcy is a thiol-containing amino acid formed during the intracellular demethylation of methionine and causes multifold effects through the reactivity of its sufhydryl group. Increase in levels of Hcy impairs cellular function and leads to loss of endothelial antithrombotic function, lipid peroxidation, impairment of platelet aggregation, enhanced oxidative stress, and apoptosis (programmed cell death) [Blom et al., 1995;Tawakol et al., 1997;Carsten and Kenneth, 2004]. These unfavorable vascular effects of Hcy are a result of the generation of reactive oxygen species (ROS) [...

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“…Increased HC levels have also been detected in obese diabetic patients (Sanchez-Margalet et al 2002). HC exerts detrimental effects on a number of cell lineages including endothelial cells (Blundell et al 1996) and neuronal cells (Kim & Pae 1996), at least partially mediated through production of reactive oxygen species (ROS; Skurk & Walsh 2004), which induce DNA damage and apoptosis (Suhara et al 2004). Studies using insulin-secreting BRIN-BD11 pancreatic beta cells demonstrated that both acute and prolonged exposure to HC had detrimental effects on beta cell glucose metabolism, insulin secretory responsiveness and cell viability (Patterson et al 2006a(Patterson et al ,b, 2007a.…”

Section: Introductionmentioning

confidence: 99%

Enhancement of homocysteine toxicity to insulin-secreting BRIN-BD11 cells in combination with alloxan

Scullion

Gurgul-Convey

Lenzen

et al. 2012

Journal of Endocrinology

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Previous studies have shown that homocysteine (HC) has a detrimental impact on insulin secretion and pancreatic beta cell function. The aim of the present study was to determine the role of reactive oxygen species (ROS) in the in vitro toxic effects of HC on insulin secretion and function of BRIN-BD11 insulin-secreting cells. In this study, insulin secretion from BRIN-BD11 cells was determined radioimmunologically, cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and glucokinase activity by a glucose phosphorylation assay following culture with HC plus alloxan (Alx). Treatment with HC resulted in concentrationdependent inhibition of insulin secretion induced by glucose and other insulinotropic agents. HC in combination with Alx resulted in a more pronounced decline in insulin secretion, including that induced by 20 mM alanine, by 43% (P!0 . 001) and 30 mM KCl by 60% (P!0 . 001), compared with control culture. The glucokinase phosphorylating capacity in cells cultured with HC plus Alx was significantly lower, compared with control cells. The cells also displayed a significant 84% (P!0 . 001) decline in cell viability. Prolonged, 72-h culture of insulin-secreting cells with HC followed by 18-h culture without HC did not result in full restoration of beta cell responses to insulinotropic agents. In vitro oxygen consumption was enhanced by a combination of Alx with HC. The study arrived at the conclusion that HC generates ROS in a redox-cycling reaction with Alx that explains the decline in viability of insulin-secreting cells, leading to reduced glucokinase phosphorylating ability, diminished insulin secretory responsiveness and cell death.

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Homocysteine Enhances Endothelial Apoptosis via Upregulation of Fas-Mediated Pathways

Abstract: Abstract-Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis. However, the underlying mechanism of endothelial cell injury in hyperhomocysteinemia has not been elucidated. In this study, we examined the effect of homocysteine (Hcy)

Cited by 80 publications

References 59 publications

Rate and determinants of progression of atherosclerosis in systemic lupus erythematosus

Rate and determinants of progression of atherosclerosis in systemic lupus erythematosus

Mitochondrial mechanism of microvascular endothelial cells apoptosis in hyperhomocysteinemia

Enhancement of homocysteine toxicity to insulin-secreting BRIN-BD11 cells in combination with alloxan

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