NO forms an adduct with serum albumin that has endothelium-derived relaxing factor-like properties.

Keaney, John F.; Simon, Daniel I.; Stamler, Jonathan S.; Jaraki, Omar; Scharfstein, Jonathan; Vita, Joseph A.; Loscalzo, Joseph

doi:10.1172/jci116364

Cited by 279 publications

(153 citation statements)

References 31 publications

(39 reference statements)

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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%

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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Section: Discussionmentioning

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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“…Albumin also exerts multiple salutary actions on vascular endothelium, helping to maintain normal microvascular permeability (He et al, 1993) and decreasing red blood cell sedimentation under low-flow conditions (Reinhart et al, 1995). Albumin reacts with nitric oxide to form a stable Snitrosothiol that has endothelium-derived relaxing factor-like properties (Keaney et al, 1993). Albumin also plays a crucial role in binding and transport of fatty acids (Curry et al, 1998).…”

Section: Part Ii: Neuroprotection --Moving From the Present Into The mentioning

confidence: 99%

Neuroprotection for ischemic stroke: Past, present and future

2008

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Neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection. Rigorously conducted experimental studies in animal models of brain ischemia provide incontrovertible proof-of-principle that high-grade protection of the ischemic brain is an achievable goal. Nonetheless, many agents have been brought to clinical trial without a sufficiently compelling evidence-based pre-clinical foundation. At this writing, around 160 clinical trials of neuroprotection for ischemic stroke have been initiated. Of the approximately 120 completed trials, two-thirds were smaller early-phase safetyfeasibility studies. The remaining one-third were typically larger (>200 subjects) phase II or III trials, but, disappointingly, only fewer than one-half of these administered neuroprotective therapy within the 4-6 hour therapeutic window within which efficacious neuroprotection is considered to be achievable. This fact alone helps to account for the abundance of "failed" trials.This review presents a close survey of the most extensively evaluated neuroprotective agents and classes and considers both the strengths and weakness of the pre-clinical evidence as well as the results and shortcomings of the clinical trials themselves. Among the agent-classes considered are calcium channel blockers; glutamate antagonists; GABA agonists; antioxidants/radical scavengers; phospholipid precursor; nitric oxide signal-transduction down-regulator; leukocyte inhibitors; hemodilution; and a miscellany of other agents. Among promising ongoing efforts, therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy are considered in detail. The potential of combination therapies is highlighted. Issues of clinical-trial funding, the need for improved translational strategies and clinical-trial design, and "thinking outside the box" are emphasized. Part I: Neuroprotection -from Past to the PresentNeuroprotection for ischemic brain injury has emerged only recently as a topic of serious biomedical inquiry. A MEDLINE survey (PubMed, 2007) reveals virtually no publications on this topic until the early 1990's but a remarkable surge in publications over the past 10 years Correspondence and reprint requests to:

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“…27,28) Moreover, GSH not only regulates the intracellular redox status but also modulates the action and metabolism of NO. 29,30) Indeed, it has been shown in cultured endothelial cells that depletion of GSH decreases synthesis of NO and reduced thiol enhances NO activity. 31,32) Consistent with the results of FMD, glucosamine administration significantly elevated the intraerythrocyte ratios of GSH/GSSG and the intraerythrocyte GSH levels.…”

Section: Discussionmentioning

confidence: 99%

Oral Administration of Glucosamine Improves Vascular Endothelial Function by Modulating Intracellular Redox State

et al. 2017

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SummaryGlucosamine, used to treat osteoarthritis, has been shown to have anti-inflammatory and antiatherosclerotic effects in experimental studies. A recent cohort study has demonstrated that the use of glucosamine was significantly associated with decreased total mortality. Vascular endothelial function is a potent surrogate marker of atherosclerosis and cardiovascular mortality where oxidative stress could participate. Therefore, we investigated whether glucosamine improves vascular endothelial function and intracellular redox state. We examined the effects of oral glucosamine administration (3000 mg/day) for 4 weeks on flow-mediated vasodilation (FMD) and intraerythrocyte glutathione parameters in 20 volunteers. Nineteen age-matched volunteers served as controls. Glucosamine administration significantly increased FMD (from 7.0 ± 2.3 to 8.7 ± 2.3%, P = 0.022). In the control group, FMD did not change. Glucosamine administration significantly increased intraerythrocyte total glutathione levels (from 212.9 ± 46.2 to 240.6 ± 49.4 μmol/L, P = 0.006), intraerythrocyte reduced form of glutathione (GSH) levels (from 124.7 ± 42.6 to 155.2 ± 47.7 μmol/L; P = 0.004) and intraerythrocyte GSH/oxidized form of glutathione (GSSG) ratios (from 3.18 ± 1.64 to 3.88 ± 1.61, P = 0.04). In the control group, any glutathione parameters did not change. Moreover, a stepwise multivariate analysis revealed percent change of GSH/GSSG is the only independent predictor for those of FMD (standardized β = 0.58, P = 0.007) in the glucosamine group. Glucosamine administration improved FMD in association with amelioration of intraerythrocyte GSH/GSSG ratios. These results suggest that oral glucosamine administration might improve vascular endothelial function by modulating intracellular redox state. (Int Heart J 2017; 58: 926-932)

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NO forms an adduct with serum albumin that has endothelium-derived relaxing factor-like properties.

Cited by 279 publications

References 31 publications

Mitochondrial mechanism of microvascular endothelial cells apoptosis in hyperhomocysteinemia

Mitochondrial mechanism of microvascular endothelial cells apoptosis in hyperhomocysteinemia

Neuroprotection for ischemic stroke: Past, present and future

Oral Administration of Glucosamine Improves Vascular Endothelial Function by Modulating Intracellular Redox State

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