Oxidation, Lipoxygenase, and Atherogenesis

Mounting evidence suggests that oxidative processes contribute to the pathogenesis of atherosclerosis and that antioxidants may represent a strategy to complement the lowering of lipids in the therapy of this disease. Although multiple molecular events have been identified in vitro and although it is tempting to ascribe multiple atherogenic properties to oxidized LDL, our understanding of this process remains incomplete. Further research is warranted in several areas. First, it will be important to selectively inhibit different aspects of the process to determine the relative contribution of various biological targets. In this regard pharmacological inhibition of 15-lipoxygenase in vivo in relevant animal models is required to address the question of the contribution of this enzyme to significant oxidative events. The lack of specific inhibitors has made this task more difficult. It will also be important to define the biologically active moiety of oxidized LDL to begin to determine the mechanisms through which it exerts its atherogenic effects. It is likely that alternate protein targets can be identified both downstream and upstream of the oxidative process. Research is only now beginning to elucidate the inflammatory mechanisms that account for the cellular response. Further research into adhesion events, cytokine profiles, and downstream effector molecules of the oxidative process are likely to identify alternate targets for therapeutic intervention.