Thrombotic complications represent a highly significant component of morbidity and mortality associated with hypercholesterolemia and atherosclerosis. In this issue of the JCI, Owens et al. report possible mechanisms underlying the prothrombotic, proinflammatory state accompanying hypercholesterolemia. Using rodent, monkey, and human subjects, they show that circulating oxidized LDL and circulating monocyte-derived tissue factor are important instigating factors driving the thrombotic, inflammatory phenotype and, surprisingly, that statin therapy ameliorated the phenotype even in the absence of lowering cholesterol levels. The studies raise the intriguing possibility that therapies directed at pathways generating oxidant stress or pathways involved in transmitting oxidized LDL–mediated signals in circulating platelets and monocytes could have antiatherothrombotic potential, probably with minimal anticoagulant and hemorrhagic potential.
Roy L. Silverstein
Atherothrombotic processes occur both within the vessel wall (neointima) and in the circulation.
In response to injury or inflammation, LDL and monocytes enter the vessel wall and become trapped. Monocytes differentiate into inflammatory macrophages that produce ROS, which oxidize trapped LDL particles to form oxLDL. These then interact with macrophages through scavenger receptors, such as CD36, activating signaling pathways that lead to enhanced inflammation and ROS generation, foam cell formation, and entrapment of the foamy macrophages to form plaque. OxLDL in the circulation interacts with blood monocytes and platelets, through CD36 and other receptors, leading to the generation of TF+ MPs and hyperreactive platelets. These create a circulating “prothrombotic state” that increases risk of acute thrombosis in the setting of unstable plaque. Statins have the potential to interrupt these processes at multiple levels by lowering circulating LDL levels, downregulating monocyte/macrophage CD36 expression, and inhibiting ROS generation and proinflammatory signaling.