Atherosclerosis anti-atherogenic effect

Another fate of arachidonic acid with potential relevance to atherosclerosis is cytochrome P450 monooxygenase-derived metabolism to epoxyeicosatrienoic acids (EETs) (Chapter 12), which may also be formed non-enzymatically by the interaction of arachidonic acid with free radicals (D.D. Gutterman, 2006). EET synthesis in cultured endothelial cells can be induced by LDL, and EETs are found both in LDL and in human atherosclerotic lesions. Biological effects of EETs include potentially anti-atherogenic effects, such as vasodilatation and prevention of platelet aggregation, and atherogenic responses, such as increased monocyte adhesion. 

Dietary intake of n-6 fatty acids such as linoleic acid, and n-3 fatty acids, such as the fish oils eicosapentanoic acid and docosahexaenoic acid, lowers plasma cholesterol and antagonizes platelet activation, but the fish oils are much more potent in this regard [26]. In particular, n-3 fatty acids competitively inhibit thromboxane synthesis in platelets but not prostacyclin synthesis in endothelial cells. These fatty acids have also been shown to have other potentially anti-atherogenic effects, such as inhibition of monocyte cytokine synthesis, smooth muscle cell proliferation, and monocyte adhesion to endothelial cells. While dietary intake of n-3 fatty acid-rich fish oils appears to be atheroprotective, human and animal dietary studies with the n-6 fatty acid linoleic acid have yielded conflicting results in terms of effects on both plasma lipoproteins and atherosclerosis. Indeed, excess amounts of both n-3 and n-6 fatty acids may actually promote oxidation, inflammation, and possibly atherogenesis (M. Toberek, 1998). In this context, enzymatic and non-enzymatic oxidation of linoleic acid in the sn-2 position of LDL phospholipids to 9- and 13-hydroxy derivatives is a key event in LDL oxidation (Section 6.2). 

Several studies on animal models demonstrated that CLA could retard the development of atherosclerosis. The CLA used in these studies was a mixture of isomers in which RA and trans-10, cis- 2-Ci%a were predominant and present in near equal amounts. Because these two isomers can show identical biological effects in some tissues and dissimilar effects in other tissues, a benefit for RA in these studies cannot be assumed. Nevertheless, there is emerging evidence that RA has anti-atherogenic properties. 

Proliferation and migration of vascular smooth muscle cells (VSMC) is one of the hallmarks of atherosclerosis. Red wine polyphenols hinder the proliferation and migration of cultured SMCs stimulated by growth factors through inhibition of PI3K activity and p38 (MAPK) phosphorylation.In support, resveratrol reversibly arrests VSMC proliferation in early S phase of the cycle. Recent studies on SMCs demonstrate the anti-atherogenic actions of resveratrol via its ability to inhibit the autocrine secretion and the mitogenic effects of endothelin-... 

The additional anti-atherosclerotic potential of a candidate compound with a different primary indication does not represent a safety concern. In contrast, the atherogenic potential of a candidate compound, identified during safety pharmacological evaluation, represents a serious safety issue. Development of atherosclerosis needs time and therefore multiple dose studies are necessary to detect a putative anti-atherosclerotic or atherogenic side effect potential of a candidate compound. 

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