Title: Nitric oxide, cardiovascular disease and dietary antioxidants


Key words: oxidative stress, atherogenesis, oxidation, LDL, low density lipoprotein, ateriosclerosis, supplements, supplementation, antioxidants, intravascular, inflammation, plaque stability, platelet adhesiveness, leucocyte, endothelial, nitric oxide, NO, synthase, NOS, vasodilation, superoxide, oxidised LDL, peroxynitrite, nitrosation, cyclo-oxygenase, vasoactive eicosanoids, intralumenal, lipid peroxidation, eNOS, iNOS, thrombosis, phenolics, vitamin C, Probucol, vitamin E, ACE inhibitors, statins, fibrinates,

Date: Sept 2006


Nutrimed Module:

Type: Article

Author: Morgan, G



Nitric oxide, cardiovascular disease and dietary antioxidants

The concept of oxidative stress as the major factor in atherogenesis is now widely accepted. The hypothesis of ‘oxidative modification’ (Steinberg 1989) states that oxidation of low density lipoproteins (LDL) in the vascular wall is the underlying cause of arteriosclerosis: the corollary is that antioxidant deficiency is associated with an increased incidence of arteriosclerosis, a fact borne out by epidemiological surveys (Gey1989,Weber 1996, Diaz 1997), and the supposition that supplementation should suppress or correct atherogenesis. Discrepancies, however, between positive results obtained in early onset arteriosclerosis in animal models and the equivocal results of human supplementation trials (Hooper 2001) have led to a reconsideration of this model of atherogenesis and a search for other pathways which might explain the experimental data.


Key events impinging on the results of supplementation trials are intravascular inflammation, plaque stability and intralumenal clotting, responses modulated by endothelial function. Nitric acid (NO), produced by endothelial nitric oxide synthase (eNOS) has been shown to inhibit leucocyte and platelet adhesiveness, the growth of smooth muscle cells and promotes vasodilation (Moncada 1993), all key factors in preventing cardiac events. Oxidative stress, a function of inflammatory change, is inversely related to antioxidant levels present in vascular tissue, including NO (Keaney & Vita 1995). Both superoxide, the major reactive oxygen species, and oxidised LDL suppress the production of NO (Chin 1992).


Overproduction of superoxide leads to peroxynitrite formation leading to lipid peroxidation, nitrosation of key proteins, tissue damage and cyclooxygenase stimulation promoting vasoconstriction and intralumenal clotting via vasoactive eicosanoids (Beckham 1996, Wolin 2000). In contradistinction to normal vasculature where low levels of superoxide, hydroxyl and alkoxyl radicals are regulated by eNOS activity (Rubbo 1994), in established atherosclerosis an isoform of NOS, inducible or iNOS, is associated with an overproduction of NO and proinflammatory effects (Grisham 1999). Genetic iNOS variants have been shown to be associated with this atherogenetic process (Hingorani 1999). Oxidative damage to lipids and proteins lead to plaque instability and with increased platelet and leucocyte adhesiveness predispose to thrombosis and acute cardiac events.


In animal models, dietary antioxidants have been shown to quench the production of reactive oxygen species such as superoxide, enabling NO to restore normal endothelial and vascular function. Atherosclerotic changes in rabbits have been reversed by increasing NO production through feeding the rabbits with the precursor L-arginine (Cooke 1992). Both vitamin E, in the rabbit (Stewart-Lee 1992), and plant phenolics in the form of red and white wine, in the rat (Flesch 1998), have produced similar results. Much laboratory work confirms the ability of vitamin C to potentiate the effects of NO (Heller 1999), possibly by acting as a superoxide scavenger or by stabilising the NO cofactor tetrahydobiopterin (Heller 2001) . In humans, however, supplementation using the NO model has been less conclusive, the greatest effect being that of vitamin C which is thought to act as a more potent vasodilator (Bult 1999, Tomasian 2000).


The data relating to NO, antioxidants and atherogenesis have been reviewed by several workers (Bult 1999). In evolved human atherosclerosis they confirm that modulation of NO by antioxidants is unable to reverse the lipid plaque changes of atherosclerosis. Positive effects mediated by NO have been noted with the strong synthetic antioxidant Probucol and to a lesser extent with vitamin C (Plane 1993), and are thought to operate by modifying endothelial function, as described. It is likely that the positive results of such trials as the CHAOS trial with vitamin E (Stephens 1996) are attributable to the same effect.


Corroborative evidence supporting this is the fact that ACE inhibitors, statins and fibrinates, which possess powerful anti-inflammatory and pro-NO effects, have been found to be highly effective in treating cardiovascular disease (Bult 1999). As with the oxidised LDL model it may be that local changes, such as reduced bioavailability of antioxidants, dislocation of prooxidant transition metal ions (Lynch 1993), elevated levels of iNOS and transcription factors such as NFkappaB, may override the benefits of antioxidant supplements. More research is indicated to clarify these issues particularly looking at NO-mediated models of atherogenesis in a younger age group.




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