Rescue of hypercholesterolemia-related impairment of angiogenesis by oral folate supplementation

Sasaki, Ken-ichiro; Duan, Jun‐Li; Murohara, Toyoaki; Ikeda, Hisao; Shintani, Satoshi; Shimada, Toshifumi; Akita, Takako; Egami, Kimiyasu; Imaizumi, Tsutomu

doi:10.1016/s0735-1097(03)00629-6

Cited by 26 publications

(18 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is interesting to note that circulating cGMP levels before folate therapy were similar to those found in type 2 diabetic patients while, after folate therapy, cGMP was significantly increased to levels found in normal subjects (41). To our knowledge, these data with regard to the effects of folate on cGMP levels have never been reported in humans but are in accordance with previous results in rats, demonstrating that ischemia-induced angiogenesis was rescued by oral folate via an NO-dependent mechanism (42). In particular, the authors found increased tissue nitric oxide and, in turn, cGMP concentrations which correlated with increased serum folate levels, supporting our data of a folate-dependent increase in cGMP levels, a new mechanism of action of folate treatment.…”

Section: Discussionsupporting

confidence: 89%

Insulin resistance and endothelial function are improved after folate and vitamin B12 therapy in patients with metabolic syndrome: relationship between homocysteine levels and hyperinsulinemia

Setola

Monti

Galluccio³

et al. 2004

European Journal of Endocrinology

140

View full text Add to dashboard Cite

Objective: The purpose of this study was (a) to study whether a folate and vitamin B12 treatment, aimed at decreasing homocysteine levels, might ameliorate insulin resistance and endothelial dysfunction in patients with metabolic syndrome according to the National Cholesterol Education Program-Adult Treatment Panel-III criteria and (b) to evaluate whether, under these metabolic conditions, there is a relationship between hyperhomocysteinemia and insulin resistance. Design and methods: A double-blind, parallel, identical placebo -drug, randomized study was performed for 2 months in 50 patients. Patients were randomly allocated to two groups. In group 1, patients were treated with diet plus placebo for 2 months. In group 2, patients were treated with diet plus placebo for 1 month, followed by diet plus folic acid (5 mg/day) plus vitamin B12 (500 mg/day) for another month. Results: In group 2, folate treatment significantly decreased homocysteine levels by 27.8% (12.2^1.2 vs 8.8^0.7 mmol/l; P , 0.01). A significant decrement was observed for insulin levels (19.9^1.7 vs 14.8^1.6 mU/ml; P , 0.01) accompanied by a 27% reduction in the homeostasis model assessment levels. A positive relationship was found between the decrement of homocysteine and insulin levels (r ¼ 0.60; P , 0.002). In parallel, endothelial dysfunction significantly improved in the treated group, since post-ischemic maximal hyperemic vasodilation increased by 29.8% and cGMP by 13.6% while asymmetrical dimethylarginine levels decreased by 21.7%. On the contrary, in group 1 patients, treated with placebo, no changes were shown in any of the variables. Conclusions: Folate and vitamin B12 treatment improved insulin resistance and endothelial dysfunction, along with decreasing homocysteine levels, in patients with metabolic syndrome, suggesting that folic acid has several beneficial effects on cardiovascular disease risk factors. European Journal of Endocrinology 151 483-489

show abstract

Section: Discussionsupporting

confidence: 89%

Insulin resistance and endothelial function are improved after folate and vitamin B12 therapy in patients with metabolic syndrome: relationship between homocysteine levels and hyperinsulinemia

Setola

Monti

Galluccio³

et al. 2004

European Journal of Endocrinology

140

View full text Add to dashboard Cite

show abstract

“…According to the results, we selected 14 days of injection because it caused significant A␤ production. Then, we injected the rats with two different dosages of Hcy (400 g/kg/day or 1600 g/kg/ day) with or without a simultaneous supplement of folate (4 mg/kg/day) and vit-B12 (250 g/kg/day) through drinking water 34 for 14 days. The injection was performed each day from 9:00 AM to 2:00 PM and the animals were sacrificed 24 hours after the final injection following measurement of spatial memory.…”

Section: Animals and Drug Administrationmentioning

confidence: 99%

Hyperhomocysteinemia Increases β-Amyloid by Enhancing Expression of γ-Secretase and Phosphorylation of Amyloid Precursor Protein in Rat Brain

Zhang

Wei

Liu

et al. 2009

The American Journal of Pathology

136

125

View full text Add to dashboard Cite

Hyperhomocysteinemia and ␤-amyloid (A␤) overproduction are critical etiological and pathological factors in Alzheimer disease, respectively; however, the intrinsic link between them is still missing. Here, we found that A␤ levels increased and amyloid precursor protein (APP) levels simultaneously decreased in hyperhomocysteinemic rats after a 2-week induction by vena caudalis injection of homocysteine. Concurrently, both the mRNA and protein levels of presenilin-1, a component of ␥-secretase, were elevated, whereas the expression levels of ␤-secretase and presenilin-2 were not altered. We also observed that levels of phosphorylated APP at threonine-668, a crucial site facilitating the amyloidogenic cleavage of APP, increased in rats with hyperhomocysteinemia, although the phosphorylation per se did not increase the binding capacity of pT668-APP to the secretases. The enhanced phosphorylation of APP in these rats was not relevant to either c-Jun N-terminal kinase or cyclin-dependent kinase-5. A prominent spatial memory deficit was detected in rats with hyperhomocysteinemia. Simultaneous supplementation of folate and vitamin-B12 attenuated the hyperhomocysteinemia-induced abnormal processing of APP and improved memory. Our data revealed that hyperhomocysteinemia could increase A␤ production through the enhanced expression of ␥-secretase and APP phosphorylation , causing memory deficits that could be rescued by folate and vitamin-B12 treatment in these rats. It is suggested that hyperhomocysteinemia may serve as an upstream factor for increased A␤ production as seen in patients with Alzheimer disease.

show abstract

“…27,28 In addition, ischemia-induced angiogenesis is reduced in eNOS knockout mice, 29 and in rat models, oral folate can rescue this process in a NO-dependent manner. 30 eNOS production of NO depends on the cofactor BH 4 . 31 The active form of folic acid, 5-methyltetrahydrofolate, restores BH 4 to allow participation in eNOS reactions.…”

Section: Psma Expression In Tumor Neovasculaturementioning

confidence: 99%

Prostate-specific membrane antigen expression in regeneration and repair

et al. 2008

View full text Add to dashboard Cite

Prostate-specific membrane antigen is a type II transmembrane glycoprotein, expressed in benign and neoplastic prostatic tissue as well as endothelial cells of neovasculature from a variety of tumors. The expression of prostate-specific membrane antigen in nonneoplastic neovasculature has not been well studied. Therefore, we studied nonneoplastic reparative and regenerative human tissues, as well as preneoplastic tissue, to determine the presence of prostate-specific membrane antigen-expressing neovasculature. Formalinfixed paraffin-embedded tissue from keloids, granulation tissue from heart valves and pleura, proliferative and secretory endometrium, and Barrett's mucosa with and without dysplasia were stained for the expression of prostate-specific membrane antigen (3E6). Vessels of proliferative, mid-secretory, and late secretory endometrium were consistently strongly positive for prostate-specific membrane antigen expression in all ten cases of each type (100%). Vessels associated with granulation tissue from pleural peels and heart valves were positive in 10 of 12 cases (83%) and 7 of 10 cases (70%), respectively. Keloids had prostate-specific membrane antigen-expressing endothelial cells in 6 of 15 cases (40%). Prostate-specific membrane antigen was not expressed by vessels associated with Barrett's mucosa with low-grade dysplasia (12 foci), high-grade dysplasia (24 foci), or no dysplasia (18 foci). A variety of nonneoplastic neovasculature expresses prostatespecific membrane antigen, including vessels in proliferative endometrium, granulation tissue, and some scars. This is the first study showing that prostate-specific membrane antigen is expressed in neovasculature from physiologic regenerative and reparative conditions. The folate hydrolase activity of prostate-specific membrane antigen may facilitate vasculogenesis and angiogenesis by increasing local availability of folic acid. These findings will enhance our overall understanding of blood vessel development and will enable us to better understand the effects of anti-prostate-specific membrane antigen therapies, which are already being explored in clinical trials.

show abstract

Rescue of hypercholesterolemia-related impairment of angiogenesis by oral folate supplementation

Abstract: Ischemia-induced angiogenesis was inhibited by HC, which was rescued by oral folate supplementation, at least in part, via an NO-dependent manner.

Cited by 26 publications

References 33 publications

Insulin resistance and endothelial function are improved after folate and vitamin B12 therapy in patients with metabolic syndrome: relationship between homocysteine levels and hyperinsulinemia

Insulin resistance and endothelial function are improved after folate and vitamin B12 therapy in patients with metabolic syndrome: relationship between homocysteine levels and hyperinsulinemia

Hyperhomocysteinemia Increases β-Amyloid by Enhancing Expression of γ-Secretase and Phosphorylation of Amyloid Precursor Protein in Rat Brain

Prostate-specific membrane antigen expression in regeneration and repair

Contact Info

Product

Resources

About