Could Direct Inhibition of Inflammation Be the “Next Big Thing” in Treating Atherosclerosis?

Abstract

The treatment of atherosclerosis during the past 2 decades has been focused on reductions in atherogenic lipids, such as low-density lipoprotein cholesterol, and, more recently, has moved toward attempting to increase high-density lipoprotein cholesterol. However, another major component of atherosclerosis is inflammation. Although long recognized in the laboratory, clinical investigators1 have more recently measured high-sensitivity C-reactive protein (hsCRP) in large clinical trials and linked higher levels with increased risk of mortality and cardiovascular events. This has led to intense interest in inflammation as a target for treatment, with the possibility that it could be the “next big thing” in managing atherosclerosis. See accompanying article on page 2256 With this information as a backdrop, the model of vascular injury used by Sarov-Blat et al2 allows initial testing of the effects of a novel antiinflammatory agent in patients with atherosclerosis. The paradigm of coronary stenting, leading to vascular injury and resulting in an inflammatory response that signals neointimal proliferation, and subsequent in-stent restenosis share many similar features of the inflammatory cascade that propagates atherosclerosis.3,4 Such extracellular stimuli are relayed to coordinated cellular responses through intracellular phosphorylation cascades, such as the mitogen-activated protein kinase (MAPK) pathways.5 So far, 4 classes of mammalian MAPK have been identified: extracellular signal–regulated kinases, c-jun N-terminal kinase or stress-activated protein kinase, extracellular signal–regulated kinase/big MAP kinase 1, and the p38 MAPKs.6 In their study, Sarov-Blat et al turn their attention to the inhibition of p38 MAPK using a newly developed agent to attenuate the inflammatory stimulus generated …