Vitamin C therapy ameliorates vascular endothelial dysfunction in treated patients with homocystinuria

Pullin, C. H.; Bonham, James R.; McDowell, Ian Frederick; Lee, P. J.; Hj, Powers; Wilson, John F.; Lewis, Malcolm J.; Moat, Stuart

doi:10.1023/a:1015672625913

Cited by 28 publications

(9 citation statements)

References 34 publications

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“…The ability of taurine to prevent inappropriate platelet aggregation in vivo may therefore be related to its ability to exert a negative cooperative effect on the high‐affinity binding of Ca 2+ to phosphatidylserine (57). Previous work has also shown that patients with HCU incur endothelial dysfunction and that this effect can be normalized by the use of the antioxidant ascorbic acid (58). Given the ability of taurine treatment to boost tissue levels of GSH, it seems possible that taurine could also ameliorate endothelial dysfunction in HCU, and this possibility is currently the subject of a human HCU patient clinical trial in our laboratory.…”

Section: Discussionmentioning

confidence: 99%

Taurine alleviates repression of betaine‐homocysteine S‐methyltransferase and significantly improves the efficacy of long‐term betaine treatment in a mouse model of cystathionine β‐synthase–deficient homocystinuria

et al. 2019

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Classical cystathionine β‐synthase‐deficient homocystinuria (HCU) is a life‐threatening inborn error of sulfur metabolism. Treatment for pyridoxine‐nonresponsive HCU involves lowering homocysteine (Hcy) with a methionine (Met)‐restricted diet and betaine supplementation. Betaine treatment efficacy diminishes significantly over time due to impairment of betaine‐Hcy S‐methyltransferase (BHMT) function. Little is known regarding the regulation of BHMT in HCU. Using a betaine‐responsive preclinical mouse model of HCU, we observed that this condition induces a 75% repression of BHMT mRNA, protein and enzyme activity, and significant depletion of hepatic betaine levels. BHMT repression was proportional to plasma Hcy levels but was not observed in mouse models of homocystinuria due to either methylenetetrahydrofolate reductase or Met synthase deficiency. Both Met supplementation and chemically induced glutathione depletion exacerbated hepatic BHMT repression in HCU mice but not wild‐type (WT) controls. Conversely, cysteine treatment normalized hepatic BHMT expression in HCU mice but had no effect in WT control animals. Taurine treatment induced BHMT expression in HCU mice by 5‐fold and restored maximal lowering of Hcy levels during long‐term betaine treatment with a concomitant normalization of inflammatory cytokine expression and a significantly improved coagulative phenotype. Collectively, our findings indicate that adjuvantial taurine treatment has the potential to significantly improve clinical outcomes in HCU.—Maclean, K. N., Jiang, H, Phinney, W. N., Keating, A. K., Hurt, K. J., Stabler, S. P. Taurine alleviates repression of betaine‐homocysteine S‐methyltransferase and significantly improves the efficacy of long‐term betaine treatment in a mouse model of cystathionine β‐synthase‐deficient homocystinuria. FASEB J. 33, 6339–6353 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Taurine alleviates repression of betaine‐homocysteine S‐methyltransferase and significantly improves the efficacy of long‐term betaine treatment in a mouse model of cystathionine β‐synthase–deficient homocystinuria

et al. 2019

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“…However, it remains possible that homocysteine affects vascular function in specific high-risk populations. For example, vitamin C improved FMD in homocystinuric patients, but it did not in control participants [ 30 ]. Therefore, our study leaves open the possibility that homocysteine is related to vascular function in specific populations, e.g., patients with cardiovascular disease or patients at high risk for cardiovascular disease.…”

Section: Discussionmentioning

confidence: 99%

Acute Effect of Folic Acid, Betaine, and Serine Supplements on Flow-Mediated Dilation after Methionine Loading: A Randomized Trial

et al. 2006

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Objectives:We investigated whether reducing post-methionine homocysteine concentrations via various treatments other than folic acid affects vascular function, as measured through flow-mediated dilation (FMD) of the brachial artery. High fasting and post-methionine homocysteine concentrations are associated with cardiovascular disease risk, but homocysteine might be a surrogate marker for low folate status.Design:This was a randomized, placebo-controlled, double-blind, crossover study.Setting:The study took place at Wageningen University in Wageningen in the Netherlands.Participants:Participants were 39 apparently healthy men and women, aged 50–70 y.Interventions:Participants ingested 10 mg of folic acid, 3 g of betaine, 5 g of serine, and placebo together with an oral methionine load. Each supplement was tested on two different days.Outcome Measures:On each of the eight treatment days, plasma homocysteine concentrations and FMD were measured before (t = 0 h, fasting) and 6 h (t = 6 h) after methionine loading.Results:The mean (± SD) fasting homocysteine concentrations averaged over the eight test days were 9.6 ± 2.1 μmol/l. Mean fasting FMD was 3.1 ± 2.4 FMD%. A methionine load with placebo increased homocysteine concentrations by 17.2 ± 9.3 μmol/l at 6 h after loading, similar to the increase following methionine loading with folic acid. A methionine load together with betaine and with serine increased homocysteine by 10.4 ± 2.8 μmol/l (p < 0.001 relative to placebo) and by 12.1 ± 8.2 μmol/l (p < 0.001 relative to placebo), respectively. Methionine loading with placebo did not affect FMD, and neither did methionine loading with folic acid, betaine, or serine; differences relative to placebo were +0.7 FMD% (95%CI, −0.6; 1.9), +0.2 FMD% (−1.0; 1.3), and +0.3 FMD% (−0.8; 1.4), respectively.Conclusions:Experimentally induced acute changes in homocysteine concentrations did not affect FMD in healthy volunteers. This implies that potential adverse effects of high homocysteine concentrations on the cardiovascular system are not mediated through vascular function. However, homocysteine or folate may affect cardiovascular disease risk through other mechanisms.

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“…Aside from the fact of vascular complications in homocystinuria, the genetic disease where levels of plasma homocysteine are higher and hyperhomocysteinemia is one of the key clinical findings, hypertension is not described [122, 123]. The vast majority of clinical as well as experimental evidences underscore the contribution of homocysteine to hypertension is secondary to its vascular effects rather than primary cause [124, 125].…”

Section: Involvement Of Thiol Homocysteine and H2s In Renovascularmentioning

confidence: 99%

Homocysteine and hydrogen sulfide in epigenetic, metabolic and microbiota related renovascular hypertension

Weber

Pushpakumar

Tyagi

et al. 2016

Pharmacological Research

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Over the past several years, hydrogen sulfide (H2S) has been shown to be an important player in a variety of physiological functions, including neuromodulation, vasodilation, oxidant regulation, inflammation, and angiogenesis. H2S is synthesized primarily through metabolic processes from the amino acid cysteine and homocysteine in various organ systems including neuronal, cardiovascular, gastrointestinal, and kidney. Derangement of cysteine and homocysteine metabolism and clearance, particularly in the renal vasculature, leads to H2S biosynthesis deregulation causing or contributing to existing high blood pressure. While a variety of environmental influences, such as diet can have an effect on H2S regulation and function, genetic factors, and more recently epigenetics, also have a vital role in H2S regulation and function, and therefore disease initiation and progression. In addition, new research into the role of gut microbiota in the development of hypertension has highlighted the need to further explore these microorganisms and how they influence the levels of H2S throughout the body and possibly exploiting microbiota for use of hypertension treatment. In this review, we summarize recent advances in the field of hypertension research emphasizing renal contribution and how H2S physiology can be exploited as a possible therapeutic strategy to ameliorate kidney dysfunction as well as to control blood pressure.

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Vitamin C therapy ameliorates vascular endothelial dysfunction in treated patients with homocystinuria

Abstract: Vitamin C ameliorates endothelial dysfunction in patients with homocystinuria, independent of changes in homocysteine concentration and should therefore be considered as an additional adjunct to therapy to reduce the potential long-term risk of atherothrombotic disease.

Cited by 28 publications

References 34 publications

Taurine alleviates repression of betaine‐homocysteine S‐methyltransferase and significantly improves the efficacy of long‐term betaine treatment in a mouse model of cystathionine β‐synthase–deficient homocystinuria

Taurine alleviates repression of betaine‐homocysteine S‐methyltransferase and significantly improves the efficacy of long‐term betaine treatment in a mouse model of cystathionine β‐synthase–deficient homocystinuria

Acute Effect of Folic Acid, Betaine, and Serine Supplements on Flow-Mediated Dilation after Methionine Loading: A Randomized Trial

Homocysteine and hydrogen sulfide in epigenetic, metabolic and microbiota related renovascular hypertension

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