El monocito/macrófago como diana terapéutica en la aterosclerosis

Monocytes and macrophages play a key role in all stages of atherosclerosis development. One of the initial phenomena in this process is binding of circulating monocytes to the arterial endothelium through adhesion molecules (AM) and their subsequent transmigration toward the intimal layer under the influence of chemokines such as monocyte chemotactic protein-1 (MCP-1). In subsequent phases, the recruited monocytes differentiate into macrophages, a process that increases the expression of toll-like receptors (TLRs), which are implicated in innate immune response, and scavenger receptors (SRs). TLRs activate the inflammatory response in macrophages, inducing the expression of cytokines such as interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF). SRs (mainly SR-A and CD36) are involved in the uptake of modified lipoproteins in a manner not regulated by intracellular sterol levels. The cholesterol taken up by macrophages through these receptors is stored in the form of cholesteryl esters after esterification by the enzyme acyl-CoA:cholesterol acyltransferase (ACAT), leading to the formation of foam cells. To maintain lipid homeostasis, macrophages depend on the existence of mechanisms of cholesterol export to the extracellular space, including transport to mature HDL mediated by the BI scavenger receptor (SR-BI) and transfer to apolipoprotein AI through the ATP-binding cassette transporter A1 (ABCA1). Pharmacological modulation of these targets (AM, cytokines, TLRs, SRs, ACAT and proteins related to cholesterol export) directly or indirectly through transcription factors controlling gene expression (liver X receptor, nuclear factor-κB) could limit the development of atherosclerosis.