Evidence suggests that
inflammation plays a central role in the pathogenesis of
atherosclerosis (Libby, Nature 420:868-874, 2002).
Inflammation is a physiologic process with highly regulated and often redundant mechanisms to balance pro-inflammatory and anti-inflammatory responses. The complexity of these networks has made it challenging to identify those specific pathways or key
enzymes that contribute directly to
atherogenesis and could act as a valuable therapeutic target.
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a member of the
phospholipase A2 family of
enzymes and is believed to contribute to
atherosclerotic plaque progression and instability by promoting
inflammation. A large number of epidemiologic studies have demonstrated that elevated levels of
Lp-PLA2 are associated with an increased risk of cardiovascular events across diverse patient populations, independent of established risk factors including
low-density lipoprotein cholesterol. Further, a growing number of preclinical and genetic studies support a causal role for
Lp-PLA2 in
atherosclerosis. The development of a novel therapeutic agent that directly inhibits the
Lp-PLA2 enzyme has provided a unique opportunity to directly test the hypothesis that inhibition of this inflammatory
enzyme will translate into improved clinical outcomes. In this article, we will review the evidence to support the notion that
Lp-PLA2 is causally implicated in the pathobiology of
atherogenesis and discuss the potential utility of inhibiting this
enzyme as a therapeutic target.