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4. Prevention of hypertension and modulation of plasma cholesterol by green tea polyphenols

Hypertension, also known as high blood pressure, is another condition linked to metabolic syndrome. Tea has been shown to reduce blood pressure and improve endothelial function in animal studies. Endothelial dysfunction is an alteration of endothelial cells, resulting from oxidative stress and impaired vasodilatory response [62]. Both hypertension and perturbed homeostasis of the ratio of HDL-cholesterol and low-density lipoprotein-associated (LDL)-cholesterol are risk factors for cardiovascular disease.

The effect of green tea extract on arterial hypertension in Sprague-Dawley rats was examined (Table 3) [63]. The animals were treated with angiotensin (Ang) II to induce to the development of hypertension. At the end of the 13 day experiment, Ang II treated rats had increased blood pressure and left ventricle mass. Co-treatment with 0.6% green tea extract as the sole source of drinking fluid blunted these increases. Green tea treatment also reduced Ang II-induced increases in plasma hydroperoxides and aortic endothelial expression of hemeoxygenase I and SOD, indicating a decrease in vascular oxidative stress.

A second study by the same group found that 0.6% green tea extract as the sole source of drinking fluid reduced final systolic and diastolic blood pressure by 20% and 24%, respectively in Ang II-treated rats after 14 d [64]. Gene expression studies in the hearts of treated rats showed that green tea extract treatment reduced Ang II induced expression of NAD(P)H oxidase expression and activity compared to Ang II-treated controls. This protein plays a key role in the induction of endothelial oxidative stress by Ang II. Similar decreases in the expression of Akt and extracellular responsive kinase (Erk) 1/2 were observed. Both enzymes are downstream effectors of NAD(P)H oxidase.

Potenza et al. examined the effect of EGCG on spontaneously hypertensive rats (SHR), a model of hypertension, insulin resistance and obesity [65]. SHR were treated for 3 weeks with EGCG (200 mg/kg/d) or enalapril (3 mg/kg/d), an angiotensin converting enzyme inhibitor that is used to treat high blood pressure and congestive heart failure. A significant decrease in systolic blood pressure in both EGCG (15% reduction) and enalapril (20% reduction) treated rats compared to SHR control. Additionally, both compounds significantly enhanced NO-induced ex vivo vasorelaxation in mesenteric vascular beds isolated from SHR. EGCG treatment also significantly decreased myocardial infarct size by 30% and improved cardiac function of SHR hearts exposed to ischemia-reperfusion injury. Mechanistic studies suggest that EGCG acts by acutely enhancing NO signaling via the phosphotidylinositol-3-kinase pathway.

By contrast, a second study in another model of spontaneous hypertension, the malignant stroke-prone spontaneously hypertensive rats (M-SHRSP), found that treatment with Polyphenon E (0.5% in the drinking fluid) for 10 wk had no effect on blood pressure, but did significantly delay onset of stroke, compared to control rats [66]. The lack of effect on blood pressure may be due to difference in this model from the SHR model, differences in dose, or some other factor.

Treatment of a type 2 diabetes rat model, the Otsuka Long-Evans Tokushima Fatty rat, with 30 mg/kg/d tea catechins for 12 weeks was shown to improve endothelial function [67]. Systolic blood pressure was reduced by 10% compared to saline-treated control rats. Catechin-treated rats also exhibited increased vasodilation in response to sodium nitroprusside treatment. These effects appear to correlate with decreased NADH oxidase expression and activity.

Green tea preparations have been shown to induce vasodilation in vitro. Using rat aortic rings, Lorenz et al. have shown that EGCG can mediate dose-dependent vasodilation [68]. These effects were abrogated by pre-treatment with Ng-nitro L-arginine methyl ester, an inhibitor of endothelial nitric oxide synthase (eNOS). On a molecular level, EGCG induced activation of Erk1/2 and Akt, and increased eNOS phosphorylation.

Green tea and green tea polyphenols have been shown to modulate plasma and tissue levels of both HDL- and LDL-cholesterol. A study in cholesterol-fed New Zealand Rabbits showed that green tea have potential anti-atherosclerotic effects [69]. Rabbits were supplemented with 3 g/L green tea (28% catechins and 10% EGCG by weight) as the sole source of drinking fluid for 21 weeks and a 31% reduction in the formation of aortic atherosclerotic lesions compared to water-treated controls. Green tea supplementation increased the lag phase for low-density lipoprotein oxidation in an ex vivo assay with the same rabbits.

Yang and Koo examined the effect of green tea supplementation on serum cholesterol levels and enzymes related to cholesterol metabolism [70]. Supplementation of Sprague-Dawley rats fed a hypercholesterolemic diet with 2 or 4% green tea for 8 weeks dose-dependently reduced total serum cholesterol (17 – 23%) and increase plasma HDL (19 – 59%) compared hypercholesterolemic diet-fed controls. Although there were no changes in the activities of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, cholesterol 7α-hydroxylase or FAS, the authors did report an increase in fecal bile acid and cholesterol levels. These results indicate that green tea can increase cholesterol excretion and elimination.

This study is somewhat contradictory to results reported by Bursill et al. which showed that supplementation of high cholesterol-fed New Zealand White Rabbits with 0.5 – 2% green tea catechins dose-dependently reduced total plasma cholesterol (60% reduction at 2% green tea catechins), plasma LDL (80% reduction at 2% green tea catechins) [71]. Similarly, liver and aortic cholesterol levels were reduced by 25%. These changes correlated with a decrease in cholesterol synthesis (60% reduction at 2% green tea catechins) and an increase in hepatic LDL receptor activity (80% increase at 2% green tea catechins) and expression (70% increase at 2% green tea catechins). The authors did not examine the specific cholesterol synthetic enzymes affected, but they did note that no change was observed in intestinal absorption of cholesterol. The differences in the results of these two studies may be the result of the use of different tea preparations or doses. More work is needed to resolve these issues.

In vitro mechanistic studies on tea polyphenols and prevention of cardiovascular disease have focused largely on the antioxidant activity of the compounds and their ability to improve endothelial function. Numerous investigators have reported that tea polyphenols can prevent the oxidation of LDL cholesterol in vitro [72-74]. For example, 1 – 10 μg/mL green tea extract was shown to dose-dependently reduce LDL oxidation induced by umbilical vascular endothelial cells [75]. A 61% reduction in LDL oxidation was observed following treatment with 10 μg/mL green tea extract. As mentioned in the previous section, some studies in animal models have confirmed these in vitro findings whereas others have not. Further clinical studies on the role of antioxidative activity of tea polyphenols in the prevention of cardiovascular disease are warranted.
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