Blinding the monocytes to protect the heart.

D espite the impressive success of statins in lowering cholesterol levels, atherosclerotic heart disease remains the leading cause of death in the Western world. Although a central role for cholesterol, particularly low-density lipoprotein cholesterol, in atherogenesis is undisputed, other contributing factors likely include diabetes mellitus, triglycerides, oxidation of proteins or lipids, and immune responses to self-or bacterial antigens. Whatever the precise agents, an expanding body of evidence strongly implicates inflammation as a final common pathway leading to the formation of unstable atherosclerotic plaques, plaque rupture, and acute myocardial infarction. Consistent with the hypothesis that inflammation plays an important role in plaque instability, a large, prospective , clinical trial found that elevated levels of high-sensitivity C-reactive protein were a strong predictor of future major car-diovascular events, even in patients who met current American Heart Association guidelines for low-density lipoprotein cholesterol levels. 3 Clinical trials are now testing the hypothesis that potent anti-inflammatory drugs, such as methotrexate 4 or interleukin-1b, 5 can reduce the risk of major cardiovascular events in patients who have suffered myocardial infarctions. Ideally, however, one would prefer a drug that more specifically targets vascular inflammation. In this regard, biological insights into the pathogenesis of atherosclerosis have focused attention on circulating blood monocytes. Landmark studies from Gerrity 6 and Faggiotto et al 7 demonstrated robust recruitment of monocytes to endothelium in swine 6 and nonhuman primates 7 within weeks of the animals being placed on high-fat diets. These monocytes are the precursors of the lipid-laden macrophage foam cells that form the fatty streak, the earliest pathological evidence of atherosclero-sis. The mechanism for monocyte recruitment was revealed by the identification of the chemokine monocyte chemoattractant protein-1 (now known as CCL2) at sites of monocyte accumulation in the vessel wall, 8 the observation that monocyte chemoattractant protein-1 is induced by minimally oxidized low-density lipoprotein, 9 and the cloning of the monocyte receptor for monocyte chemoattractant protein-1 (CCR2). 10 Genetic deletion of CCR2, 11 or monocyte chemoattractant protein-1, 12 markedly diminished atherosclerotic lesion formation in mice placed on high-fat diets, providing compelling evidence that the monocyte chemoattractant protein-1/CCR2 axis mediated the directed migration of monocytes to areas destined to accumulate foam cells and subsequently develop atherosclerosis. More recent work has demonstrated significant heterogeneity among monocytes and their potentially different roles in ath-erogenesis. 13 Proinflammatory monocytes, identified by high expression of the surface marker Ly6C, are CCR2 +. 14 A second monocyte subset, …