By now, the reader will have gained an appreciation for the important role of oxidative stress in many of the responses observed in both acute and chronic hypercholesterolemic states. Thus, it follows that strategies targeting these oxidant-generating systems or their products could have immense therapeutic potential in the reduction of hypercho-lesterolemia-induced atherosclerosis. While animal studies have shown great promise, the use of antioxidant therapies, such as vitamins C and E, in humans has yielded disappointing results (62). Vitamins C and E have been shown to enhance antioxidant levels, prevent eNOS downregulation and improve endothelial function in several animal models (63). This may lead to reduced atherosclerotic plaque for mation (64). While there have been relatively few positive findings or mechanistic insights with vitamin therapy in humans, the use of slow-release vitamins was recently found to delay the progression of atherosclerotic lesion development (65). However, high levels of certain vitamins may also alter the blood lipid profile in a manner that could outweigh any antioxidant benefit (66). Interestingly, evidence is emerging that drugs developed for other purposes, for example HMG-CoA reductases (statins), AT1 receptor antagonists, aspirin, and 17P-estradiol, possess properties that reduce oxidative stress independently or as a result of their targeted action. The most extensively investigated of these, i.e., statins and AT1 receptor antagonists, are discussed below.
Statins were first introduced as lipid-lowering drugs, by virtue of their blocking action on the conversion of HMG-CoA to mevalonoate, the substrate for cholesterol. However, recently, it has become increasingly apparent that statins exert many anti-inflammatory properties that extend beyond their cholesterol-lowering effect. For example, several statins have been shown to increase eNOS expression and subsequently endothelial NO production (67). Furthermore, there is evidence that statins may reduce oxidant production both by preventing enzyme activation, in particular NAD(P)H oxidase activation (68), and by increasing levels of antioxidants such as catalase (55). This would lead to a diminished oxidant stress, and possibly offer an explanation for the ability of statins to attenuate transcription factor activation, reduce CAM expression and cytokine release, and ultimately inhibit leukocyte and platelet recruitment in a cholesterol level-independent manner.
Interest in the angiotensin-converting enzyme inhibitors and AT1 receptor antagonists is increasing, as these agents appear to have therapeutic potential in areas other than hypertension. In particular hypercholesterolemia, which promotes AT1 receptor induction (52,53,69), may be a clinically viable target. In fact, AT1 receptor antagonists have been shown to attenuate atherosclerotic lesion development (56). Since angiotensin activates several subunits of
NAD(P)H oxidase via the ATI receptor (51), and ATI receptor antagonists can increase NO release from platelets and endothelial cells (70), this treatment may result in an overall reduction of oxidative stress during hypercholesterolemia. Therefore, the actions of this class of drugs may extend beyond their blood pressure-lowering effects. It is noteworthy that statins are capable of reducing the overexpression of AT1 receptors caused by angiotensin II in hypercholesterolemic humans (69).
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