(−)-Epicatechin Activation of Endothelial Cell Endothelial Nitric Oxide Synthase, Nitric Oxide, and Related Signaling Pathways

Abstract

Abstract-Recent reports indicate that (Ϫ)-epicatechin can exert cardioprotective actions, which may involve endothelial nitric oxide synthase (eNOS)-mediated nitric oxide production in endothelial cells. However, the mechanism by which (Ϫ)-epicatechin activates eNOS remains unclear. In this study, we proposed to identify the intracellular pathways involved in (Ϫ)-epicatechin-induced effects on eNOS, using human coronary artery endothelial cells in culture. Key Words: flavonoids Ⅲ ischemia Ⅲ polyphenols Ⅲ endothelial cells Ⅲ endothelial nitric oxide synthase C ardiovascular diseases (CVD) are is a leading cause of morbidity and mortality, affecting Western industrialized countries as well as developing countries. 1,2 CVD imposes major direct and indirect costs on health care systems, ranging from hospitalizations, drugs, and rehabilitation services to losses of productivity due to premature mortality and short-and long-term disability. 1 The incidence of CVD continues to increase; thus, it is important to identify potential therapeutic agents to prevent and treat CVD.CVD is importantly linked to endothelial cell dysfunction. Endothelial cell dysfunction is associated with conditions, such as obesity, smoking, diabetes, and hormonal changes. The vascular endothelium mediates many important physiological functions, such as responses to shear stress, angiogenesis, vascular remodeling, inflammation, and coagulation. It also participates in metabolic and synthetic processes. 3 A key modulator of endothelial cell activity is nitric oxide (NO), which under physiological conditions is mainly produced by the endothelial nitric oxide synthase (eNOS) isoform. NO regulates vascular tone, proliferation of vascular smooth muscle cells, and hemostasis, among other important functions. Disruptions in the physiological production of NO triggers endothelial cell dysfunction, resulting in an increased susceptibility to CVD. 4 Therefore, strategies aimed at "physiologically" increasing NO bioavailability are promising for the prevention and therapy of CVD.The induction of NO synthesis by flavonoid-containing compounds has received widespread attention, as their effects appear to positively impact CVD. Epidemiological studies indicate that the regular dietary intake of plant-derived foods and beverages high in flavonoids is inversely associated with the incidence of CVD. 5 Although these compounds are pleiotropic in nature, many of their effects may be explained by improving endothelial function. The regular consumption of cacao products high in flavonoid content has also been demonstrated to provide beneficial cardiovascular effects. 5 Natural cacao products are rich in monomeric and polymeric forms of the flavonoids (Ϫ)-epicatechin (EPI) and catechin (60/40 ratio) and can contain up to 10% flavonoids by weight. 6 The consumption of cacao products can ameliorate

Vasculoprotective Effects of Dietary Cocoa Flavanols in Patients on Hemodialysis

“…The exact mechanisms through which CF exerts putative cardioprotective effects still remain incompletely elucidated. Effects on NO homeostasis with increased nitrosothiol plasma levels, cellular signal cascades, altered gene expression, and enzyme activity are considered potential pathways (19,47). In this study, we did not observe differences in plasma nitrite or nitrate levels, possibly because of small sample size or activation of inducible NO synthase as suggested for patients with ESRD (50).…”

“…The mechanisms by which CFs mediate their effects are not fully understood. An enhancement in NO bioactivity through increases in NO synthase activity has been shown along with enhanced endothelial homeostatic vascular repair capabilities and activation of signaling pathways (19,20).…”

Dose-dependent increases in flow-mediated dilation following acute cocoa ingestion in healthy older adults

“…Specifically, increased FMD resulting from cocoa/chocolate ingestion are reversed by NO synthase inhibition (16,22) and circulating biomarkers of NO synthesis are increased (19,22,42). Additionally, flavanols appear to increase endothelial-derived NO synthase activity (30,35) and lower vascular arginase activity (39). If NO production was increased by cocoa, we have no evidence that this was mediated by an antioxidant effect of cocoa, as we observed no change in oxidized LDL levels.…”

Effects on Peripheral and Central Blood Pressure of Cocoa With Natural or High-Dose Theobromine

“…10 Flavanols and their metabolites may reduce BP by angiotensin-converting enzyme inhibition, 11 nicotinamide adenine dinucleotide phosphate-oxidase activity inhibition, 12 and stimulating the release of nitric oxide (NO). 10,13 Additionally, theobromine, which is invariably present in cocoa in high concentrations, could also contribute to the antihypertensive effect of cocoa. 14,15 Theobromine is thought to have vasodilating properties by inhibition of phosphodiesterase.…”