Hypothesis articleCardioprotective effects of vegetables: Is nitrate the answer?
Introduction
Our diet exerts important long-term effects on vital body functions and thereby makes an important contribution to health and disease. While high intake of cholesterol, saturated fat, salt, and sugar are generally associated with a greater risk for cardiovascular disease conventional wisdom has it that the opposite is true for abundant consumption of fruits and vegetables [1]. However, surprisingly few studies have evaluated the relationship between fruit and vegetable intake and cardiovascular disease. Recently, a number of large epidemiological studies have attempted to address this issue [1], [2], [3], [4]. Joshipura et al. [3], [5] found that a high intake of fruits and vegetables was indeed associated with a reduced risk for coronary heart disease and ischemic stroke. The large study population also allowed for analysis of the protection afforded by specific types of foods, and the strongest protection against coronary heart disease was seen with high intake of green leafy vegetables. In another study, Appel et al. [6] looked at the effects of dietary supplementation with vegetables on blood pressure in subjects with borderline hypertension. They found that intake of vegetables decreased blood pressure almost to the same extent as monotherapy with a standard antihypertensive drug. The specific nature of the active constituent(s) responsible for the cardioprotective effects of vegetables is still unknown although fiber, minerals, and antioxidants have all been proposed as viable candidates [1], [2]. In the midst of the current hype about the possible significance of polyphenolic antioxidants in protecting organs from the sequelae of oxidative stress, we here wish to put forward an alternative and disarmingly simple hypothesis: We propose that the high content of inorganic nitrate is a major factor contributing to the positive health effects of certain vegetables via bioconversion to nitrite, nitric oxide (NO), and other secondary reaction products (nitroso/nitrosyl compounds), all of which may exert protective effects on the cardiovascular system.
Section snippets
An alternative pathway for NO generation
Continuous generation of NO is essential for the integrity of the cardiovascular system, and a decreased production and/or bioavailability of NO is central to the pathogenesis of cardiovascular disorders including atherosclerosis, hypertension, and ischemic heart disease [7], [8]. The classical pathway for generation of NO in mammals is via NO synthases present, for example, in the vascular endothelium. These enzymes produce NO from the precursor amino acid, l-arginine, and molecular oxygen.
Nitrite protects the cardiovascular system
While the notion that nitrite and nitrate may be beneficial rather than detrimental to human health is not entirely new [9], [10], [21], [22], [23], [24], much of these discussions evolved around direct antimicrobial effects of acidified nitrite in the GI tract and on the skin. Although long-term toxicological studies in rats have not confirmed that nitrite or nitrate are carcinogenic, and epidemiological studies have failed to provide a causal link between nitrate intake and cancer [25], [26],
Bioconversion of dietary nitrate to nitrite and NO
Nitrate has been used for food preservation purposes since centuries. Largely out of safety concerns in relation to the formation of potentially carcinogenic nitrosamines and the formation of methemoglobin in infants these days maximally allowable concentrations of nitrite and nitrate in drinking water are strictly regulated in Europe, the US, and many other countries. However, the by far dominating dietary source (>80%) of nitrate is the ingestion of vegetables [31]. Green leafy vegetables
Testing the hypothesis
A combination of experimental studies and clinical trials will allow us to determine if dietary nitrate does indeed provide the purported protection against cardiovascular disease. Several animal models of cardiovascular disease may readily lend themselves to intervention studies with nitrate. In this context, the use of germ-free animals may prove very useful. In theory, such animals should have no benefit from nitrate supplementation as they cannot convert dietary nitrate into bioactive
Conclusion
We here propose that the protective effect of certain vegetables on the cardiovascular system is related to their high content of nitrate. The mechanism involves reduction of dietary nitrate to nitrite, nitric oxide, and possibly other biologically active reaction products in a process that requires cooperation with symbiotic bacteria in the oral cavity. A continuous intake of nitrate-containing food such as green leafy vegetables may ensure that tissue levels of NO and other nitrogen/nitrosyl
Acknowledgments
The authors have received grants from the European Commission 6th Framework Program (Eicosanox LSHM-CT-2004-005033), the Swedish Heart and Lung Foundation, the Swedish Research Council, the Ekhaga Foundation and the National Institutes of Health (NHLB). These organizations had no role in designing or writing of this paper.
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