Fatty acids act on vascular endothelial cells and influence the development of cardiovascular disease.

Endothelial cells (ECs) maintain the health of blood vessels and prevent the development of cardiovascular disease (CVD). Free saturated fatty acids (FAs) induce EC damage and increase the risk of CVD by promoting arteriosclerosis. Conversely, polyunsaturated FAs (PUFAs), such as docosahexaenoic acid, are thought to suppress EC damage induced during the early stages of CVD. This review describes the effects of multiple dietary FAs on EC disorders involved in the development of CVD. The roles of FAs in atherosclerosis and CVD were analyzed by evaluating articles published in PubMed, Science Direct, and Web of Science. Saturated FAs were found to induce EC damage by reducing the production and action of EC-derived nitric oxide. Oxidative stress, inflammation, and the renin-angiotensin system were found to be involved in EC disorder. Furthermore, n-3 PUFAs were found to reduce EC dysfunction and prevent the development of EC disorder. These results indicate that FAs may affect EC failure induced during the early stages of CVD and reduce the risk of developing the disease.

Dietary docosahexaenoic acid inhibits neurodegeneration and prevents stroke.

Stroke severely impairs quality of life and has a high mortality rate. On the other hand, dietary docosahexaenoic acid (DHA) prevents neuronal damage. In this review, we describe the effects of dietary DHA on ischemic stroke-associated neuronal damage and its role in stroke prevention. Recent epidemiological studies have been conducted to analyze stroke prevention through DHA intake. The effects of dietary intake and supply of DHA to neuronal cells, DHA-mediated inhibition of neuronal damage, and its mechanism, including the effects of the DHA metabolite, neuroprotectin D1 (NPD1), were investigated. These studies revealed that DHA intake was associated with a reduced risk of stroke. Moreover, studies have shown that DHA intake may reduce stroke mortality rates. DHA, which is abundant in fish oil, passes through the blood-brain barrier to accumulate as a constituent of phospholipids in the cell membranes of neuronal cells and astrocytes. Astrocytes supply DHA to neuronal cells, and neuronal DHA, in turn, activates Akt and Raf-1 to prevent neuronal death or damage. Therefore, DHA indirectly prevents neuronal damage. Furthermore, NDP1 blocks neuronal apoptosis. DHA, together with NPD1, may block neuronal damage and prevent stroke. The inhibitory effect on neuronal damage is achieved through the antioxidant (via inducing the Nrf2/HO-1 system) and anti-inflammatory effects (via promoting JNK/AP-1 signaling) of DHA.

Prevention of Endothelial Dysfunction and Cardiovascular Disease by n-3 Fatty Acids-Inhibiting Action on Oxidative Stress and Inflammation.

BACKGROUND: Prospective cohort studies and randomized controlled trials have shown the protective effect of n-3 fatty acids against cardiovascular disease (CVD). The effect of n-3 fatty acids on vascular endothelial cells indicates their possible role in CVD prevention. OBJECTIVE: Here, we describe the effect of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on endothelial dysfunction-caused by inflammation and oxidative stress-and their role in the development of CVD. METHODS: We reviewed epidemiological studies done on n-3 fatty acids in CVD. The effect of DHA and EPA on vascular endothelial cells was examined with regard to changes in various markers, such as arteriosclerosis, inflammation, and oxidative stress, using cell and animal models. RESULTS: Epidemiological studies revealed that dietary intake of EPA and DHA was associated with a reduced risk of various CVDs. EPA and DHA inhibited various events involved in arteriosclerosis development by preventing oxidative stress and inflammation associated with endothelial cell damage. In particular, EPA and DHA prevented endothelial cell dysfunction mediated by inflammatory responses and oxidative stress induced by events related to CVD. DHA and EPA also increased eNOS activity and induced nitric oxide production. CONCLUSION: The effects of DHA and EPA on vascular endothelial cell damage and dysfunction may involve the induction of nitric oxide, in addition to antioxidant and anti-inflammatory effects. n-3 fatty acids inhibit endothelial dysfunction and prevent arteriosclerosis. Therefore, the intake of n-3 fatty acids may prevent CVDs, like myocardial infarction and stroke.

Protective Effect of Epigallocatechin Gallate on Endothelial Disorders in Atherosclerosis.

Healthy vascular endothelial cells regulate vascular tone and permeability, prevent vessel wall inflammation, enhance thromboresistance, and contribute to general vascular health. Furthermore, they perform important functions including the production of vasoactive substances such as nitric oxide (NO) and endothelium-derived hyperpolarizing factors, as well as the regulation of smooth muscle cell functions. Conversely, vascular endothelial dysfunction leads to atherosclerosis, thereby enhancing the risk of stroke, myocardial infarction, and other cardiovascular diseases (CVDs). Observational studies and randomized trials showed that green tea intake was inversely related to CVD risk. Furthermore, evidence indicates that epigallocatechin gallate (EGCG) found in green tea might exert a preventive effect against CVDs. EGCG acts as an antioxidant, inducing NO release and reducing endothelin-1 production in endothelial cells. EGCG enhances the bioavailability of normal NO by reducing levels of the endogenous NO inhibitor asymmetric dimethylarginine. Furthermore, it inhibits the enhanced expression of adhesion molecules such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 and attenuates monocyte adhesion. In addition, EGCG prevents enhanced oxidative stress through the Nrf2/HO-1 pathway. These effects indicate that it might prevent the production of reactive oxygen species, inhibit inflammation, and reduce endothelial cell apoptosis during the initial stages of atherosclerosis. The current review summarizes recent research in this area and discusses novel findings regarding the protective effect of EGCG on endothelial dysfunction and CVDs in general.

A phytoestrogen supplement prevents the altered gene expression associated with pregnancy implantation induced by IL-1ß in endometrial epithelial cells.

Phytoestrogens stimulate expression of the uterine estrogen receptor and regulate uterine functions in reproductive tissues. However, comprehensive understanding of the beneficial impacts of phytoestrogens on uterine biology at the molecular level remains unexplored. Interleukin-1ß (IL-1ß) expression is increased in the inflamed decidua and is associated with first trimester pregnancy loss. AglyMax-Sup has the same composition as that of the phytoestrogen supplement AglyMax but with added vitamins and other components. Expression of genes associated with implantation may be enhanced by AglyMax-Sup compared with AglyMax. We tested the hypothesis that AglyMax-Sup has greater effects on implantation compared with AglyMax, using RT-PCR and Western blotting in the endometrial epithelial cell line. Furthermore, we investigated the protective effect of AglyMax-Sup on IL-1ßinduced changes in estrogen-responsive gene expression in endometrial epithelial cells. The purpose of this study was to compare the effects of the phytoestrogen supplement AglyMax-Sup with those of AglyMax on estrogen-responsive gene expression. AglyMax and AglyMax-Sup significantly (p<0.05) induced gene expression of glycodelin-A, HoxA10, IL-11, LIF, MEG-E8 and TGFß1. AglyMax-Sup induced high levels of these genes compared with the levels induced by AglyMax. The enhanced expression of LIF, IL-11, integrin αV, and HOXA10 induced by AglyMax-Sup was abolished by the ER antagonist fulvestrant and the ERK inhibitor PD98059. Meanwhile, IL-1ß inhibited progesterone plus estrogen-induced TGFß1, glycodelin-A, HOXA10, and integrin αV expression. IL-1ß-induced suppression of these expression was reversed by AglyMax-Sup. These results indicate that expression of genes associated with implantation may be increased by AglyMax-Sup compared with AglyMax. AglyMax-Sup might abrogate IL-1ß-mediated changes that can affect embryo implantation via the MAPK pathway.

Epigallocatechin-3-gallate inhibits VCAM-1 expression and apoptosis induction associated with LC3 expressions in TNFα-stimulated human endothelial cells.

Tumor necrosis factor alpha (TNF-α) promotes the expression of adhesion molecules and induces endothelial dysfunction, a process that can lead to atherosclerosis. Green tea consumption can inhibit endothelial dysfunction and attenuate the development of arteriosclerosis. The purpose of this study was to examine whether epigallocatechin-3-gallate (EGCG) prevents TNF-α-dependent endothelial dysfunction. Here, we compared the regulatory effects of the green tea components EGCG and L-theanine against TNF-α-induced stimulation of adhesion molecule expression and apoptosis induction, which is associated with autophagy. Monocytic cell adhesion to human endothelial cells was measured using a fluorescently-labeled cell line, U-937. Caspase 3/7 activity was examined with a fluorescent probe and fluorescence microscopy. In addition, we analyzed the expression of several genes by RT-PCR. TNF-α-modulation of LC3 and VCAM1 protein levels were investigated by Western blot (WB). TNF-α induced adhesion of U937 cells to endothelial cells, and gene expression associated with adhesion molecules and apoptosis. On the other hand, EGCG and L-theanine inhibited TNF-α-induced adhesion of U937 cells to endothelial cells and inhibited increases in ICAM1, CCL2 and VCAM1 expression. Furthermore, EGCG and L-theanine inhibited TNF-α-induced apoptosis-related gene expression (e.g., CASP9), and caspase activity while inhibiting TNFα-induced VCAM1, LC3A and LC3B protein expression. Meanwhile, treatment of endothelial cells with autophagy inhibitor 3-methyladenine (3-MA) blocked EGCG-induced expression of CASP9. Together, these results indicate that EGCG can modulate TNF-α-induced monocytic cell adhesion, apoptosis and autophagy. We thus conclude that EGCG might be beneficial for inhibiting TNF-α-mediated human endothelial disorders by affecting LC3 expression-related processes.

ß-carotene reverses the IL-1ß-mediated reduction in paraoxonase-1 expression via induction of the CaMKKII pathway in human endothelial cells.

Interleukin-1 beta (IL-1ß) induces endothelial dysfunction and reduces nitric oxide (NO) production. IL-1ß also enhances adhesion molecule expression and induces arteriosclerosis. Conversely, high-density lipoprotein (HDL) induces endothelial NO synthase (eNOS), paraoxonase-1 (PON-1) activity, and maintains vascular health. Diet-derived ß-carotene prevents arteriosclerosis, but its mode of action is not understood. The purpose of this study was to examine the HDL-like mechanisms of ß-carotene in endothelial cells. We added IL-1ß and/or ß-carotene to cultured human endothelial cells and examined its effects on the regulation of HDL signal transduction pathways using RT-PCR, real-time PCR, Western blot (WB), and endothelial-U937 adhesion analysis. IL-1ß decreased the expression of Ca2+/calmodulin-dependent kinase II (CaMKII), eNOS, PON-1, phosphatidylinositol 3-kinase (PI3K), PSD-95/Dlg/ZO-1 (PZK1), and liver kinase B1 (LKB1). Conversely, it increased the expression of intercellular adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein 1 (MCP-1). In contrast, ß-carotene increased the expression of CaMKKII, PI3K, PZK1, LKB1, eNOS, PON-1, and reduced the expression of ICAM-1 and MCP-1. ß-carotene also induced phospho-AMP-activated protein kinase (p-AMPK), phospho-eNOS and PON-1 proteins. Importantly, ß-carotene upregulated the IL-1ß-mediated decrease of CaMKKII, PZK1, LKB1, eNOS and PON-1. ß-carotene inhibited IL-1ß-mediated cell adhesion of U937 to endothelial cells. The effect of ß-carotene was reversed by a CaMKK inhibitor, STO-609. These findings indicate that ß-carotene regulates the expression of PON-1, eNOS and adhesion molecules via CaMKK pathway activation. ß-carotene may contribute to the functional maintenance of vascular endothelial cells in a manner similar to HDL, protecting them against stimuli such as IL-1ß.

Stability to light, heat, and hydrogen peroxide at different pH values and DPPH radical scavenging activity of acylated anthocyanins from red radish extract.

The stability of red radish extract to light, heat, and hydrogen peroxide at different pH values (3, 5, and 7) was examined, in which major anthocyanins were pelargonidin glycosides acylated with a combination of p-coumaric, ferulic, or caffeic acids. The light irradiation (fluorescence light, 5000 lx; at 25 degrees C) indicated that the red radish extract was more stable at lower pH than at higher pH. The HPLC analyses revealed that diacylated anthocyanins in the extract were more stable to light at pH 3 than monoacylated anthocyanins. No significant difference in degradation rates of acylated anthocyanins at pH 5 was observed, whereas anthocyanins acylated with p-coumaric or ferulic acids were more stable at pH 7 than ones with caffeic acids. The stability to heat (at 90-95 degrees C) showed a tendency similar to that for light. The number of intramolecular acyl units contributes to stability to light and heat at lower pH, whereas the characteristics of intramolecular acyl units influence the stability at higher pH. The degradation behavior of red radish extract to H2O2 were almost the same to those of light and heat, depending on the pH. However, HPLC analyses revealed that the stability of individual acylated anthocyanins were independent of the pH. These data suggest that the characteristics, the number, and the binding site of intramolecular acyl units affect the stability of anthocyanin to H2O2. DPPH radical scavenging activity of all acylated anthocyanins was higher than those of pelargonidin and perlargonidin-3-glucoside. The activity of acylated anthocyanins mostly depended on the activity of intramolecular acyl units (caffeic acid > ferulic acid > p-coumaric acid). However, the activity was highly affected by the binding site of intramolecular acyl units even if anthocyanins have common acyl units.