Folates and Cardiovascular Disease

Verhaar, Marianne C.; Stroes, Erik S.G.; Rabelink, Ton J.

doi:10.1161/hq0102.102190

Cited by 263 publications

(185 citation statements)

References 141 publications

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“…16 Additionally, folates may facilitate the binding of tetrahydrobiopterin to eNOS. 15,16 Finally, it has been speculated that 5-methyltetrahydrofolate may mimic tetrahydrobiopterin at its receptor site on eNOS or may facilitate the electron transfer to produce NO. 15,27 There are certain limitations to our study.…”

Section: Discussionmentioning

confidence: 99%

“…10,14 In fact, 5-methyltetrahydrofolate, the active metabolite of folic acid, may have direct effects on uncoupled eNOS, which results in increased release of NO and decreased release of superoxide anion. 13,15,16 Thus, there may be a rationale for considering the use of folates to restore NO availability in situations such as diabetes where there is a relative deficiency of active tetrahydrobiopterin. Indeed, van Etten et al 17 demonstrated that an acute arterial infusion of 5-methyltetrahydrofolate could restore impaired endothelium-dependent vasodilatation as assessed by forearm plethysmography in patients with type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

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Folic acid improves endothelial dysfunction in type 2 diabetes - an effect independent of homocysteine-lowering

Title

Giddens

et al. 2006

Vasc Med

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Diabetes is associated with endothelial dysfunction, which in part may be related to uncoupling of the endothelial nitric oxide (NO) synthase enzyme, thus reducing the availability of NO. As folates may potentially reverse the uncoupling of NO synthase, we wanted to determine whether folic acid supplementation could modulate endothelial function and markers of inflammation in patients with type 2 diabetes without vascular disease. Nineteen patients with type 2 diabetes were treated with folic acid (10 mg/day for 2 weeks) versus placebo in a randomized, placebo-controlled, cross-over study with an 8-week washout period between treatments. Fasting endothelium-dependent flow-mediated dilatation (FMD) of the brachial artery, endothelium-independent nitroglycerin-mediated dilatation (NMD), plasma homocysteine, serum lipids, folate, and inflammatory markers (high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, interleukin-18, tumor necrosis factor-alpha) were assessed after each 2-week treatment period. Folic acid supplementation significantly increased folate levels and lowered plasma homocysteine levels. Folic acid significantly improved FMD compared to placebo (5.8 Ϯ 4.8% vs 3.2 Ϯ 2.7%, p ϭ 0.02). There were no significant effects of folic acid supplementation on lipids, NMD, or the inflammatory markers. There was no relationship between the change in homocysteine and the improvement in FMD. Thus, 2 weeks of folic acid supplementation can improve endothelial dysfunction in type 2 diabetics independent of homocysteinelowering, but does not modulate markers of inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Folic acid improves endothelial dysfunction in type 2 diabetes - an effect independent of homocysteine-lowering

Title

Giddens

et al. 2006

Vasc Med

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“…32,33 Folic acid and its metabolites are also superoxide radical scavengers. 34,35 The Role of PSMA in Vasculogenesis Cellular folate gradients across cell membranes are maintained by the g-glutamylated form, polyglutamyl folate, which accumulates intracellularly, and must be deconjugated by pteroylpoly-g-glutamate hydrolase, also called folate hydrolase, into a monoglutamylated form to participate in metabolic reactions. 36 PSMA has folate hydrolase activity.…”

Section: Psma Expression In Tumor Neovasculaturementioning

confidence: 99%

Prostate-specific membrane antigen expression in regeneration and repair

et al. 2008

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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.

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“…Guo et al15 found that FA therapy could significantly improve endothelial function. Most studies of the relationship between FA and atherosclerosis have focused on FA's ability to reduce serum homocysteine levels 24 or on FA's antioxidant,7 anti‐inflammatory11 and antithrombotic effects 14. Little is known regarding the regulatory effects of FA on VSMC dedifferentiation, which is necessary for the development and progression of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Folic acid delays development of atherosclerosis in low‐density lipoprotein receptor‐deficient mice

Pan

Liu

Gao

et al. 2018

J Cellular Molecular Medi

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Many studies support the cardioprotective effects of folic acid (FA). We aimed to evaluate the utility of FA supplementation in preventing the development of atherosclerotic in low‐density lipoprotein receptor‐deficient (LDLR−/−) mice and to elucidate the molecular processes underlying this effect. LDLR−/− mice were randomly distributed into four groups: control group, HF group, HF + FA group and the HF + RAPA group. vascular smooth muscle cells (VSMCs) were divided into the following four groups: control group, PDGF group, PDGF + FA group and PDGF + FA + RAPA group. Blood lipid levels, oxidative stress and inflammatory cytokines were measured. Atherosclerosis severity was evaluated with oil red O staining. Haematoxylin and eosin (H&E) staining was used to assess atherosclerosis progression. Immunohistochemical staining was performed with antismooth muscle α‐actin (α‐SMA) antibodies and anti‐osteopontin (OPN) antibodies that demonstrate VSMC dedifferentiation. The protein expression of α‐SMA, OPN and mechanistic target of rapamycin (mTOR)/p70S6K signalling was detected by Western blot analysis. FA and rapamycin reduced serum levels of total cholesterol, triacylglycerol, LDL, inhibiting oxidative stress and the inflammatory response. Oil red O and H&E staining demonstrated that FA and rapamycin inhibited atherosclerosis. FA and rapamycin treatment inhibited VSMC dedifferentiation in vitro and in vivo, and FA and rapamycin attenuated the mTOR/p70S6K signalling pathway. Our findings suggest that FA attenuates atherosclerosis development and inhibits VSMC dedifferentiation in high‐fat‐fed LDLR−/− mice by reduced lipid levels and inhibiting oxidative stress and the inflammatory response through mTOR/p70S6K signalling pathway.

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Folates and Cardiovascular Disease

Abstract: Abstract-It

Cited by 263 publications

References 141 publications

Folic acid improves endothelial dysfunction in type 2 diabetes - an effect independent of homocysteine-lowering

Folic acid improves endothelial dysfunction in type 2 diabetes - an effect independent of homocysteine-lowering

Prostate-specific membrane antigen expression in regeneration and repair

Folic acid delays development of atherosclerosis in low‐density lipoprotein receptor‐deficient mice

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