Objective
Reactive species of oxygen and nitrogen mediate the oxidative modification of low-density lipoprotein (LDL). Oxidation of LDL is inhibited by endogenous radical scavenging enzymes such as MnSOD and Cu/ZnSOD that catalyze dismutation of O2- to H2O2. Cu/ZnSOD but not MnSOD is inactivated by H2O2. Low molecular antioxidants such as uric acid regulate this inactivation. As the reduction of SOD activity progresses, superoxide could react more easily with NO to produce peroxynitrite, resulting in an increase in OxLDL. Here we evaluated whether a focal imbalance between pro- and antioxidant systems induces plaque vulnerability in patients with carotid stenosis.
Methods and Results
Carotid plaques from 35 patients who underwent carotid endarterectomy were classified as vulnerable or stable based on histopathological findings. In vulnerable plaques, OxLDL, measured by sandwich ELISA was significantly higher (p<0.01) and the SOD activity significantly lower than in stable plaques (p<0.05). The plaque and plasma OxLDL level were inversely correlated with plaque SOD activity (p<0.01). There was a significant correlation between plaque and plasma OxLDL levels (p<0.01). The physiological uric acid level in all plaques was one-fourth to one-eight of that in plasma and appeared to be unable to protect Cu-ZnSOD from degradation by H2O2. Immunohistochemical methods disclosed increased peroxinitrite and OxLDL in vulnerable plaques. The present findings suggest that once the oxidative status overwhelms the antioxidative defense system, the oxidation progresses rapidly. Although more patients with vulnerable plaques were symptomatic than patients with stable plaques, the difference was not statistically significant. and also their stenosis was almost similar. However, plaque and plasma OxLDL levels in symptomatic patients (n=13) with vulnerable plaque were significantly higher than those in asymptomatic patients (n=9) with stable plaque (31.9±19.4 ng/μg of apoB and 0.26±0.063 vs 3.96±2.14 and 0.142±0.036; p<0.01). On the other hand, plaque SOD activity in symptomatic patients with vulnerable plaque were significantly lower than in asymptomatic patients with stable plaque (48.2±8.1% vs 73.3±6.6%; p<0.01).
Conclusion
Our results suggest that a focal imbalance between pro- and antioxidant defense systems in patients with carotid plaques induces an increase in plaque OxLDL levels and consequent plaque instability, and contributes to the high levels of plasma OxLDL.