Coenzyme Q And Atherosclerosis

9.4.1 Levels of a-TOH and CoQ10H2 in Plasma of Patients with Cardiovascular Disease

As CoQ10H2 is the first lipoprotein-associated antioxidant consumed when plasma is exposed to various oxidizing conditions, it has been proposed that the plasma coenzyme Q10 redox status [i.e., CoQ10H2/(CoQ10H2 + CoQ10)] may represent a useful diagnostic indicator for in vivo lipoprotein oxidation and oxidative stress.74 A number of studies have compared the levels of CoQ10H2 in the plasma of patients with advanced atherosclerosis with that of age-matched controls. On average, plasma CoQ10H2 and the coenzyme Q redox status are slightly lower, and the levels of a-TOH slightly higher in patients exhibiting clinical indices of coronary artery disease.101,102 Importantly, these changes in plasma antioxidant levels were not significant.101 There also appears to be no significant difference in the levels of antioxidants in isolated LDL from patients and controls, and hydroperoxides of cholesteryl esters were undetectable (detection limit 10 nM) in both patients and controls.101 Thus, plasma and LDL levels of lipophilic antioxidants, including CoQ10H2, appear only partially oxidized even in subjects with severe atherosclerosis.101,102 Overall, this is consistent with the assumption that oxidized lipoproteins detected in atherosclerotic lesions are derived primarily from oxidation reactions occurring within the arterial wall.

In contrast to coronary artery disease patients, a significant decrease in the plasma coenzyme Q10 redox status has been reported for patients with hyperlipidemia, liver disease (hepatitis, hepatoma, cirrhosis), or treated with percutaneous transluminal coronary angioplasty.75,103 105

9.4.2 Is TMP Relevant for In Vivo Lipid Oxidation during Atherosclerosis?

Whether TMP of lipoprotein lipids occurs in vivo is difficult to prove. However, various lines of evidence suggest that lipid oxidation detected in atherosclerotic lesions occurs in the presence of a-TOH, and in part, via TMP.23 Thus, oxidants thought to promote LDL oxidation in vivo promote LDL lipid peroxidation in vitro via TMP. Also, substantial amounts of oxidized lipids coexist with normal levels of a-TOH.95 106 In addition, 60 to 70% of cholesteryl linoleate alcohols (Ch 18:2-OH), the predominant lipid oxidation products present in human atherosclerotic lesions95 107 are present as the nonenzymatic and thermodynamically unfavorable cis, trans-isomers.23 This indicates that they were formed in the presence of a-TOH.108 109 Finally, where examined, coantioxidants inhibit aortic lipoprotein lipid peroxidation in the aortas of atherosclerosis prone animals.12110 Together, these findings are consistent with, though are not conclusive proof that oxidation of lipoprotein lipids in the atherosclerotic lesions occurs primarily via TMP. The findings are largely inconsistent with the common assumption that substantial LDL lipid oxidation requires depletion of a-TOH.49 Given the important consequences, more work is required to establish whether, and if so to what extent, lipoprotein lipid oxidation occurs in the absence or presence of vitamin E.

9.4.3 Coenzyme Q10 Content in Atherosclerotic Lesions

With respect to inhibition of in vivo lipid peroxidation during atherogenesis, CoQ10H2 is a prime candidate as an in vivo (co-) antioxidant for a number of reasons. First, unlike aqueous coantioxidants, CoQ10H2 is incorporated in lipoproteins, and as such can exhibit site-specific coantioxidation. Second, CoQ10H2 inhibits LDL lipid peroxidation induced by both strong and mild oxidizing conditions18 (S. R. Thomas and R. Stocker, unpublished observations). Third, CoQ10H2 is a first line of lipophilic antioxidant defense in lipoproteins and plasma against physiologically relevant oxidants. Fourth, supplementation with coenzyme Q increases the lipoprotein's content of CoQ10H2 from <1 to >1 molecule per particle and this increases the oxidation resistance (see above). Finally, coenzyme Q

appears to be a safe dietary supplement with no reported side effects, although long-term studies with relatively high doses (100 to 200 mg/day) remain to be carried out.

In atherosclerotic lesions, CoQ10H2 has not been detected despite normal concentrations of total coenzyme Q being present.95 However, any remaining CoQ10H2 may have autoxidized during sample preparation. If coenzyme Q is present predominantly as CoQ10 in the arterial wall, then this would increase the susceptibility of lipoproteins to oxidation. A recent study111 using apolipoprotein E knockout mice fed a high fat diet has reported that aortic coenzyme Q content decreases proportionally to a-TOH as the atherosclerotic lesions develop. This, too, may increase the susceptibility of lipoprotein lipids to oxidation.18 However, dietary supplementation of these mice with coenzyme Q10 can increase aortic coenzyme Q up to 10 times thereby rectifying the imbalance with a-TOH seen in unsupplemented mice.62

9.4.4 Does Coenzyme Q10 Supplementation Attenuate Experimental Atherosclerosis?

Recent studies have shown that supplementation of atherosclerosis susceptible apo-E gene knockout mice with coenzyme Q10 results in substantially increased plasma and aortic levels of CoQ10H2.62 Importantly, this was associated with a decrease in the concentration of aortic lipid hydroperoxides and the extent of atherosclerosis in the aorta (P. K. Witting, K. Pettersson, R. Stocker, in preparation). In light of the oxidation theory, it might be assumed that the ability of CoQ10H2 to inhibit aortic lipid oxidation is the primary reason for its antiatherosclerotic activity. However, a recent study has shown that aortic lipid oxidation and atherosclerosis can be dissociated12 and antioxidants may inhibit atherosclerosis independent of LDL oxidation.1124 Further studies are required to validate the antiatherogenic activity of coenzyme Q.

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