Anti-inflammatory therapeutics for the treatment of atherosclerosis

Abstract

Atherosclerosis is the primary cause of heart disease and stroke and is thus the underlying pathology of the leading causes of death in the western world. Although risk can be reduced by lowering lipid levels, the equally important contribution of inflammation to the development of cardiovascular disease is not adequately addressed by existing therapies. Here, we summarize the evidence supporting a role for inflammation in the pathogenesis of atherosclerosis, discuss agents that are currently in the clinic and provide a perspective on the challenges faced in the development of drugs that target vascular inflammation.

Figure 1. Model of an atherosclerotic plaque showing some of the key inflammatory mechanisms involved

Monocytes are first recruited to developing plaques by chemoattractants, such as chemokine CC motif ligand 2 (CCL2; also known as MCP1) and leukotriene B4 (LTB4). Following this, they differentiate into macrophages, which accumulate oxidized low-density lipoprotein (LDL) and become foam cells. The macrophages release chemotactic factors, which attract additional monocytes and thus set up a positive feedback loop, as well as leukotriene C4 (LTC4), which increases vascular permeability. Activated macrophages and foam cells secrete metalloproteinases and tissue factor, which degrade the fibrous plaque, leading to plaque rupture and thrombosis. CCR2, chemokine CC motif receptor 2; CysLTR, cysteinyl leukotriene receptor; Lp-PLA2, lipoprotein-associated phospholipase A2; LTB4R, leukotriene B4 receptor 1; sPLA2, secretory phospholipase A2.

Figure 2. The phospholipase A2 pathways that result in the generation of foam cells and atherogenic lipids, and the leukotriene pathway with enzymatic steps depicted

a | Secretory phospholipase A2 (sPLA2) interacts with circulating low-density lipoprotein (LDL) particles and modifies LDL, thereby reducing liver uptake of LDL by the LDL receptor. Both sPLA2 and lipoprotein-associated PLA2 (Lp-PLA2) interact with more oxidized forms of LDL to generate bioactive lipids. b | The cysteinyl leukotrienes increase vascular permeability and induce smooth muscle cell proliferation. Leukotriene B4 (LTB4) induces leukocyte chemotaxis into the atherosclerotic plaque. 5-LO, arachidonate 5-lipoxygenase; cPLA2, cytoplasmic PLA2; FLAP, 5-LO-activating protein; LTA4, leukotriene A4; LTA4H, LTA4 hydrolase; LTC4, leukotriene C4, LTC4S; LTC4 synthase; LTD4, leukotriene D4; LTE4, leukotriene E4; Lyso-PC, lysophosphatidylcholine; Ox-FA, oxidized fatty acids.