The potential for novel anti-inflammatory therapies for coronary artery disease

Key Points Although drugs that lead to cholesterol and lipid lowering have proved to have significant effects in lowering cardiovascular morbidity and mortality, coronary artery disease remains a principal cause of death worldwide. So, there is a clear need for the discovery of additional therapeutic approaches to control this disease adequately. In addition to therapies that target novel mechanisms of regulating lipid metabolism, recent data indicate that targeting the inflammatory process in the developing vascular plaques could be beneficial. The recruitment, activation and differentiation of monocytes/macrophages to the sub-endothelial space of the nascent vascular lesion, and their subsequent differentiation to lipid-laden foam cells, is the key inflammatory pathway that leads to the development of advanced, necrotic, unstable plaques. Mouse genetics has been used to evaluate the importance of various pathways that are used in the transport of monocytes and macrophages to vascular lesions. A key step in this process is the secretion of inflammatory cytokines, chemoattractants and other reactive molecules from the vascular endothelium and underlying smooth muscle layer after activation by lipids or lipoproteins. These inflammatory molecules stimulate the endothelium to synthesize adhesion molecules, which results in the selective attraction of activated platelets and monocytes to the activated endothelial surface. Mouse studies indicate that low-affinity interactions of selectins and integrins with their cognate ligands might mediate the initial attraction of these circulating vascular cells to the endothelial layer. These low-affinity interactions lead to a slowing, or rolling, of the cells on the endothelium. High-affinity interactions with activated integrins lead to arrest, or firm adherence, of the cells to the endothelial surface. Current data indicate that the E- and P-selectins, as well as vascular cell adhesion molecule 1 (VCAM-1) and the α4β1-integrin (also known as very late (activation) antigen 4; VLA-4), are responsible for mediating rolling and firm arrest of leukocytes on the endothelial surface. After arrest, monocytes migrate across the endothelium in response to a gradient of chemoattractant. The chemokine MCP-1, through its interaction with the monocyte chemokine (CC) motif receptor 2 (CCR2), seems to have an important role in this process. These data indicate that the antagonism of one or more of these monocyte-transport pathways co