Oxidative Stress and Cardiovascular Disease

This post will focus on the potential roles of fat-soluble nutrients and fat-soluble antioxidants in preventing cardiovascular disease (CVD). Two fat-soluble vitamins will be discussed in detail, i.e. vitamin E and vitamin D. Vitamin E (tocopherols and tocotrienols) is generally considered an antioxidant nutrient, although it may have important functions unrelated to its antioxidant functions (as discussed below). Antioxidant nutrients function by preventing damage to biological systems caused by reactive oxygen species (ROS) and/or reactive nitrogen oxide species (RNOS). Vitamin D (calciferols) is not a true vitamin since it is not required in our diet, can be produced in skin tissue, and is generally not present in plants. Vitamin D is, perhaps, best described as a steroid hormone precursor. Although vitamin D may function as a membrane antioxidant under in vitro conditions (Wiseman, 1993), its primary biological role is to maintain plasma calcium and phosphorus homeostasis.

The additional fat-soluble antioxidant nutrient reviewed here will be coenzyme Q10 (ubiquinone or CoQ10), which has strong antioxidant properties. Vitamin E and CoQ10 can protect lipid±protein complexes, such as biological membranes and lipoproteins, from lipid peroxidation. During lipid peroxidation, highly reactive lipid hydroperoxides, peroxyl radicals and reactive aldehydes, such as malondialdehyde (MDA) and 4-hydroxynonenol (4-HNE), are generated. The peroxyl radicals support chain reactions that can rapidly damage oils, biological membranes or lipoproteins containing polyunsaturated fatty acids (PUFA).

The literature reviewed below strongly suggests that oxidative stress plays a key role in the etiology of cardiovascular disease. Oxidative stress is a physiological condition in which pro-oxidant factors outweigh antioxidant defences. Accordingly, the role of oxidative stress in promoting cardiovascular disease and the roles of fat-soluble antioxidant nutrients in potentially protecting from this disease process will be discussed in some detail. Oxidative stress is likely to occur during inflammatory processes, during exercise and from cigarette smoking. The evidence presented below also suggests that vitamin D plays an important and significant role in preventing cardiovascular disease but it is very unlikely that this effect is related to its potential role as an antioxidant.

Owing to the enormous worldwide impact of cardiovascular disease it must be emphasized that even very modest reductions in risk factors, brought about by the appropriate design and use of functional foods, can have very important health related and economic significance. Statistics from the American Heart Association (see http://www.americanheart .org /statistics/03cardio.html) indicate the enormous impact of CVD. Over 61 million Americans have one or more types of CVD. CVD causes more mortality each year than the next seven leading causes of death combined and the estimated cost of cardiovascular diseases and stroke in the United States in 2003 was $352 billion. In developed countries, childhood obesity has reached epidemic proportions and this will certainly translate into a dramatic increase in type 2 diabetes which is charac­terized by elevated levels of triglycerides, LDL-C (low-density lipoprotein­ cholesterol) and decreased levels of HDL-C (high-density lipoprotein­ cholesterol), i.e. a shift towards a highly atherogenic lipid profile. Moreover, the World Health Organization (see http://www.who .int/ncd/cvd ) makes a very convincing argument that CVD impact is not just limited to Westernized countries but will reach epidemic proportions in developing countries as well because of demographic and lifestyle changes. It has been estimated that by the year 2020, CVD will be the number one cause of deaths in the world.

Both lipid-soluble and water-soluble antioxidants present in blood may be important in preventing cardiovascular disease owing to their ability to prevent the oxidation of lipid—protein complexes called lipoproteins. Lipoproteins are extremely important in cardiovascular disease since we know with certainty that high levels of LDL-C cause atherosclerosis, which is the underlying cause of most cardiovascular disease. In contrast, high levels of HDL-C are a negative risk factor for CVD. Atherosclerosis is the gradual build-up of `plaque’ in the arterial wall. LDL-C is the major source of the lipids occurring in these plaques.

There is now considerable evidence that LDL lipids (primarily cholesteryl esters) make their way into plaques by cells in the arterial wall called macrophages. These macrophages take up so much LDL that they become `foamy’ in appearance and are, therefore, called `foam cells.’ This is the very first step (called fatty streak formation) in atherosclerosis and this process begins in childhood. It is surprising, however, that LDL incubated with macrophages does not transform into foam cells. After LDL is oxidized (oxLDL) it will, however, cause macrophages to transform into foam cells. Macrophages have receptors for native LDL but the expression of these receptors is down-regulated by the accumulation of intracellular cholesterol. Unlike native LDL, chemically modified forms of LDL can be taken up by scavenger receptors whose expression is not down-regulated by the accumulation of intracellular cholesterol.

LDL is the primary plasma carrier for both vitamin E and CoQ10, both of which act as antioxidants in LDL by inhibiting lipid peroxidation of lipids containing polyunsaturated fatty acid moieties. Work by Jessup et al. (1990) indicates that most of the endogenous vitamin E in LDL must be oxidized before it is converted into a `high uptake’ form of oxLDL capable of transforming macrophages into foam cells. Since antioxidants, such as vitamin E, prevent the oxidation of LDL (Jessup et al., 1990) it is logical to suggest that antioxidants could prevent foam cell formation and thereby retard the process of atherosclerosis. This suggestion is called the `oxidative modification hypothesis.’ Although most in vitro experiments support this view, not all evidence is supportive (Asmis and Jelk, 2000).

Whether or not oxLDL formation occurs in vivo and what the mechanism (s) might be for this oxidation are still open issues (Chisolm and Steinberg, 2000). Despite intensive efforts, there is little evidence for the existence of oxLDL in fresh human plasma. This has led to the hypothesis that LDL could be oxidized in the subendothelial space of arteries rather than in plasma. It is significant, therefore, that LDL isolated from human aortic atherosclerotic intima has extremely high levels of 3-nitrotyrosine (Leeuwenburgh et al., 1997). Although the origin of this 3-nitrotyrosine is not clear, it is probably due to the reaction of peroxynitrite (ONOO) with tyrosine residues in apoB100 (the primary protein component of LDL). The addition of ONOO to LDL or bovine serum albumin in vitro certainly gives rise to 3-nitrotyrosine. Furthermore, LDL-treated ONOO undergoes lipid peroxidation accompanied by the oxidation of alpha­tocopherol to alpha-tocopheryl quinone and is converted to a form recognized by macrophage scavenger receptors (Graham et al., 1993; Hogg et al., 1993).

If oxLDL were the source of lipids in atherosclerotic plaques one might expect that these lipids would have a very low content of vitamin E. Paradoxically, Suarna et al. (1995) have found that human atherosclerotic plaques contain relatively large amounts of alpha-tocopherol and ascorbate (a water-soluble antioxidant). Foam cells are not likely, therefore, to be formed by the uptake of large amounts of oxLDL with very low levels of endogenous tocopherol. Nevertheless, Suarna et al. (1995) also found that plaque contains large amounts of oxidized lipids and a significant level of alpha-tocopheryl quinone, an oxidation product of alpha-tocopherol. These data support the view that oxidative stress is an important factor in atherosclerosis but indicate that oxidized lipids in atherosclerotic plaques may not be derived from oxLDL.