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,3
* Center for Vascular Medicine and Department of Metabolic Diseases, Medical Policlinic, City Campus, University of Munich Medical Center, Munich, Germany
3 To whom correspondence should be addressed: E-mail: norbert.weiss{at}med.uni-muenchen.de.
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ABSTRACT |
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 TOP ABSTRACT DISCUSSIONLITERATURE CITED |
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KEY WORDS: • aged garlic extract • hyperhomocysteinemia • endothelial function • nitric oxide • oxidant stress
The clinical problem. Mildly elevated plasma homocysteine concentrations, those above 12 µmol/L, are frequently found in Western populations and are associated with an increased risk of cardiovascular disease. On the basis of a metaanalysis of prospective clinical studies conducted to 2002, the presence of mild hyperhomocysteinemia is associated with a relative risk of 1.49 (95% CI 1.31–1.70) for coronary heart disease and a relative risk of 1.37 (95% CI 0.99–1.91) for cerebrovascular disease (1). Mild hyperhomocysteinemia has also been associated with peripheral arterial occlusive disease (2) and venous thromboembolism (3). Whether or not this association is causative remains a subject of debate. Several arguments, however, weigh in favor of hyperhomocysteinemia as a causative cardiovascular risk factor, as discussed recently (4).
Current treatment options for hyperhomocysteinemia include supplementation of folic acid and vitamin B-12. This treatment is efficient in normalizing plasma homocysteine levels and improving endothelial function in most patients with hyperhomocysteinemia and normal renal function (5). Whether or not this reduction in plasma homocysteine levels translates into a reduced risk for cardiovascular disease is still unclear.
In addition, not all hyperhomocysteinemic patients reduce plasma homocysteine in response to B-vitamin supplementation. In particular, patients with chronic renal failure, who have a dramatically increased risk of cardiovascular disease at least partly mediated by increased plasma homocysteine levels, do not sufficiently respond to folic acid and vitamin B-12 supplementation (6). Therefore, alternative treatment strategies are needed.
Antioxidant treatment strategies are a promising alternative for high-risk patients, especially patients with chronic renal failure. Although supplementation with antioxidants has not been shown to be effective in decreasing cardiovascular risk in primary and secondary prevention studies in the general population (7,8), 2 clinical studies in patients with end-stage renal disease have documented a significant reduction in cardiovascular events following supplementation with either vitamin E (9) or N-acetylcysteine (10).
Endothelial dysfunction caused by decreased bioavailability of nitric oxide as a key event in the vascular pathobiology associated with hyperhomocysteinemia. The pathobiological mechanisms that lead to the atherogenic propensity associated with hyperhomocysteinemia suggest that a key target of elevated homocysteine levels is the vascular endothelium, where it produces endothelial dysfunction and structural endothelial injury (5,11). By its complex endocrine and paracrine functions, functionally intact endothelium exerts potent antiatherothrombotic effects (12). In contrast, endothelial dysfunction, which may be characterized as an imbalance between vasorelaxing and -contracting substances, between pro- and anticoagulant factors, between pro- and antiinflammatory mediators, and between inhibitors and promotors of vascular cell growth, plays a crucial role in the pathogenesis and progression of atherothrombotic vascular disease (5,13). A key component of endothelial dysfunction is an impairment of the endothelium-dependent regulation of vascular tone, which is indicative of a reduction in the bioavailability of the endothelium-derived signaling molecule nitric oxide (NO)4 (14,15). This molecule is released from endothelial cells in response to increased shear stress (16) and certain biochemical stimuli (17) such as acetylcholine or bradykinin. Besides regulating vascular tone, endothelium-derived NO is able to mediate most of the other antiatherothrombotic functions of the endothelium (18). Therefore, a reduction in the bioavailability of NO constitutes an important step in the pathobiology of atherosclerotic vascular disease.
An impairment of endothelium-dependent vasodilation can be detected in chronic hyperhomocysteinemic subjects free of overt cardiovascular disease (19–21) as well as in healthy subjects during acute hyperhomocysteinemia induced by an oral methionine challenge (22–27). Homocysteine-induced endothelial dysfunction is thought to decrease bioavailable NO through oxidative inactivation. Hyperhomocysteinemia leads to increased vascular oxidant stress through an increase in the oxidation rate of plasma aminothiols that is accompanied by the generation of reactive oxygen species and, more importantly, by a NO synthase–dependent generation of superoxide anion (28). This increased formation of reactive oxygen species is further amplified by a homocysteine-specific decrease in the activity of important antioxidant enzymes such as superoxide dismutase (29,30) and the cellular isoform of glutathione peroxidase (31–33). Conversely, boosting antioxidant capacity, either by pretreatment with antioxidants such as vitamin E or vitamin C (24,25,34,35), by increasing the cellular content of reduced glutathione (33), or by overexpressing the cellular isoform of glutathione peroxidase (36), can prevent endothelial dysfunction following an oral methionine challenge or restore endothelial dysfunction in hyperhomocysteinemic humans and in animal models of chronic hyperhomocysteinemia.
Role of the cellular redox state in regulating endothelial function in hyperhomocysteinemia. In this context, we are especially interested in the role of the cellular antioxidant system of glutathione and glutathione peroxidase in regulating endothelial function. It has been previously demonstrated that this system is crucial for maintaining normal endothelial function. The deletion of cellular glutathione peroxidase is associated with increased vascular oxidant stress and endothelial dysfunction in an animal model. The negative effects of deleting cellular glutathione peroxidase activity can be overcome by increasing cellular glutathione levels (37). As mentioned above, mildly hyperhomocysteinemic mice have decreased activity of cellular glutathione peroxidase and endothelial dysfunction. Boosting cellular glutathione levels by pharmacological methods (33) or increasing cellular glutathione peroxidase activity by genetic means (36) can normalize endothelial function in these mice. More recently, it has been demonstrated that the cellular redox status not only is important for maintaining normal endothelial-dependent vascular reactivity but also influences the interaction between endothelial cells and circulating mononuclear cells, a critical step in the development of atherosclerotic lesions (38).
Pharmacological methods for increasing cellular glutathione levels in humans so far consist of treatment with N-acetylcysteine or L-2-oxothiazolidine-4-carboxylic acid (OTC). The latter has been shown to improve endothelial function in a mouse model of hyperhomocysteinemia (33) and in humans with coronary artery disease and multiple cardiovascular risk factors (39). However, the safety of long-term administration of OTC in humans has not yet been studied and cannot yet be recommended.
Impact of aged garlic extract on the cellular redox state and on nitric oxide bioavailability. Aged garlic extract (AGE), manufactured by Wakunaga Pharmaceutical Co., is a garlic preparation uniquely produced by a natural aging process of up to 20 mo. During this process, the odorous, harsh, and irritating compounds in garlic are converted naturally into stable and safe sulfur compounds. AGE contains primarily water-soluble sulfur compounds such as S-allylcysteine and S-allylmercaptocysteine, as well as a variety of oil-soluble sulfur compounds (40). These compounds may act as cellular donors of thiol-containing reducing equivalents comparable to N-acetylcysteine or OTC.
Numerous bioactivities have been attributed to AGE or S-allylcysteine since 1955. These include antioxidant properties (41–43), at least partly related to modulation of the glutathione redox cycle (44,45). These properties translate into an inhibition of Cu2+-induced LDL oxidation (46,47) and a protection of endothelial cells from oxidized LDL-induced injury by preventing intracellular depletion of reduced glutathione and by minimizing release of peroxides from endothelial cells and macrophages (48). In addition, it has been shown that AGE enhances the production of endproducts of endothelium-derived NO in mice (49) and improves blood flow in humans (50), presumably by increasing bioavailable NO metabolites derived from endothelial NO synthase (49). This conclusion is supported by in vitro findings that showed that AGE and S-allylcysteine significantly increased cyclic guanosine monophosphate production by endothelial NO synthase in human umbilical-vein endothelial cells (51). All these effects seem to translate into antiatherosclerotic properties in animal models of atherosclerosis (52,53). More recently, it has been shown that AGE inhibits the rate of progression of coronary calcification as measured by electron beam tomography in patients with coronary artery disease (54).
AGE has been marketed for more than 40 y as an over-the-counter medicine in Japan and in more than 30 other countries for longer than 10 y. Since 1955, the worldwide cumulative use of AGE is estimated to be around 1.5 million treatment days. Toxicity with acute or chronic treatment with AGE has not been reported (40).
Effect of aged garlic extract on macro- and microvascular endothelial dysfunction during acute hyperhomocysteinemia. To study whether supplementation with AGE has the potential to reverse or attenuate endothelial dysfunction induced during acute hyperhomocysteinemia after an oral methionine challenge, we performed a double-blind placebo-controlled crossover intervention trial with AGE supplementation in 11 healthy subjects aged 25 to 40 (5 female, 6 male). The study protocol complied with the declaration of Helsinki on ethical principles for medical research involving human subjects as revised in 1983, and informed consent was obtained from all participants.
Study participants were free of overt cardiovascular disease, free of cardiovascular risk factors, and took no cardiovascular medications, vitamins, or antioxidant supplements. Subjects were randomized to either a placebo or AGE (4 mL/d) for a 6-wk intervention period, followed by a 6-wk washout phase. Subjects taking the placebo were crossed over to the active treatment group for another 6 wk, and vice versa. Before and at the end of each intervention period, endothelial function in a large conductance vessel (the brachial artery) and in small resistance vessels (the forearm skin microcirculation) was studied. Measurements were taken before and 4 h after an oral methionine load (0.1 g/kg body weight) to induce acute hyperhomocysteinemia.
To study endothelium-dependent vasoreactivity in the macrocirculation, the diameter of the brachial artery was measured with a high-resolution vascular ultrasound device equipped with a 7.5-kHz linear array transducer (Accuson 128XP/10, Siemens Medical Solutions USA) both before and during reactive hyperemia, as described previously (55). Reactive hyperemia was induced by a blood-pressure cuff positioned at the forearm distal to the brachial artery and inflated to suprasystolic levels for 5 min. The flow-mediated dilation (FMD) during reactive hyperemia, observed 45–60 s after sudden deflation of the cuff, is a well-established parameter for endothelium-dependent vasodilation and represents an increased release of endothelium-derived vasodilatory NO. To control for any effects of the experimental procedure or the oral methionine challenge on endothelium-independent vasodilation, measurements of the diameter of the brachial artery were repeated 4 min after application of sublingual nitroglycerin, which acts directly on vascular smooth muscle cells.
Microvascular endothelial function was studied by measuring skin perfusion at the volar side of the forearm using a laser-Doppler instrument (Periflux 5001, Perimed AB) equipped with a solid-state diode laser probe (780 nm). Flux was recorded at baseline and after application of acetylcholine or sodium nitroprusside by iontophoresis with a micropharmacology delivery system (Perilont, Perimed AB), as described previously (56).
Safety of the intervention was monitored both clinically and by performing routine clinical laboratory examinations including full blood counts and liver- and kidney-function tests.
Treatment with AGE was well tolerated, without any side effects that could be detected clinically or by routine clinical chemical analysis. The oral methionine load, as expected, resulted in an 
4.5-fold increase in plasma homocysteine concentrations at baseline examinations in both groups and at the follow-up examination in the placebo-treated subjects. AGE treatment had no influence on fasting homocysteine levels, but it slightly, although significantly, attenuated the increase in plasma homocysteine concentrations after an oral methionine load by around 27% in AGE-treated subjects compared with placebo-treated subjects.
Acute hyperhomocysteinemia induced by an oral methionine challenge led to a significant decrease in flow-mediated vasodilation to 35–49% compared with the food-deprived state in the baseline examinations in both groups, as well as in the follow-up examination in the placebo-treated group (P < 0.01 for all 3 groups) (Fig. 1). Acute hyperhomocysteinema, however, had no effect on endothelium-independent vasodilation after application of nitroglycerin. This reproduces several previous studies (22–27) and indicates a decreased bioavailability of endothelium-derived NO during acute hyperhomocysteinemia. In subjects pretreated with AGE, flow-mediated vasodilation was no longer different between measurements in food-deprived and postmethionine subjects (91 ± 47% of flow-mediated vasodilation in the fasting state), representing a 66% increase in flow-mediated vasodilation during acute hyperhomocysteinemia in AGE-treated subjects compared with placebo-treated subjects (P < 0.05 vs. placebo). This indicates that pretreatment with AGE at least partly compensates for the adverse effects of homocysteine on endothelial function and NO bioavailability.
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DISCUSSION |
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TOPABSTRACTDISCUSSIONLITERATURE CITED |
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The presence of atherosclerotic lesions is associated with endothelial dysfunction manifested as impaired endothelium-dependent regulation of vascular tone (59–62). In patients with atherosclerotic risk factors, impaired endothelial vasodilator function is notable early in the process of atherogenesis, even before the development of frank atherosclerotic lesions. Its extent is related to the intensity and duration of risk-factor exposure, and treatment of risk factors results in reversal or attenuation of endothelial dysfunction (63–65). Clinical studies have demonstrated that the presence of endothelial vasodilator dysfunction in conductance vessels such as coronary arteries or the brachial artery is a predictive marker for the future development of coronary artery disease in patients with cardiovascular risk but angiographically normal coronary arteries at baseline (64). Furthermore, endothelial dysfunction is associated with a worse prognosis in existing coronary artery disease and with predicting coronary disease progression and cardiovascular event rates (66,67). These findings underscore the central role of the endothelium in vascular function and its regulation and suggest that the endothelium is both a target and a mediator of the process of atherothrombosis. Improving endothelial function therefore might have the potential to attenuate the process of atherosclerotic lesion development, even independent of modification of the cardiovascular risk-factor profile. This hypothesis, however, has not been studied yet. Because AGE has been shown to improve endothelial function, further studies should be performed into whether improving endothelial function may reduce the progression of atherosclerosis and result in a lower cardiovascular event rate. There is preliminary evidence from a recent clinical pilot study that AGE is able to inhibit the progression of coronary calcifications as measured by electron-beam tomography in patients with coronary artery disease who are already on maximum standard therapy, including statins, ß blockers and aspirin (54).
AGE has also been shown to improve microvascular endothelial function, at least in the setting of acute hyperhomocysteinemia. In this context it is worth mentioning that abnormalities in microvascular endothelial function seem to be especially involved in the pathogenesis of microvascular complications in diabetic subjects, including those with diabetic neuropathy and foot ulcers (68,69). This leads to the question whether or not AGE may have the potential to improve microvascular endothelial function, especially in diabetic subjects, and whether this may lead to a reduction in microvascular complications.
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FOOTNOTES |
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2 Author disclosure: No relationships to disclose.
4 Abbreviations used: AGE, aged garlic extract; EDHF, endothelium-derived hyperpolarizing factors; FMD, flow-mediated dilation; NO, nitric oxide; OTC, L-2-oxothiazolidine-4-carboxylic acid.
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