Mast cells in vulnerable atherosclerotic plaques--a view to a kill

Abstract

The aim of the present review is to discuss the participation of mast cells in the pathogenesis of erosion and rupture of atherosclerotic plaques, the major causes behind acute coronary syndromes and myocardial infarction. We present ex vivo observations describing mast cells and their activation in human atherosclerotic plaques and discuss in vitro and in vivo data showing that mast cells are potential regulators of inflammation, immunity and adverse remodeling, including matrix remodeling and cell death. Furthermore, we focus on studies that have been performed with human tissues and human mast cells, but when appropriate, we also discuss observations made in animal models. Finally, we present potential pharmacological means to modulate mast cell responses in the arterial vessel walls.

1

Diet-induced atherosclerosis is attenuated in mast cell-deficient mice. To test the role of mast cells in the pathogenesis of atherosclerosis in vivo, mast cell-deficient mice (Kit^W-sh/W-sh) were crossed with LDLR-deficient mice (LDLR^−/−) to obtain a LDLR^−/−/Kit^W-sh/W-sh double knockout mouse model. As shown in Figure 1, the extent of aortic atherosclerosis that is induced in an LDLR^−/−/Kit^+/+ mouse (A) by a Western-type diet for 9 weeks is slightly attenuated in an LDLR^−/−/Kit^W-sh/W-sh mouse (B).

2

A role for mast cells in the intra- and extracellular accumulation of low density lipoprotein (LDL) cholesterol in atherogenesis. Upon activation, the mast cell secretes its preformed granules by exocytosis into the subendothelial space of the arterial intima. Histamine, a mast cell-derived soluble mediator increases the transendothelial transport of plasma LDL into the subendothelial space, where it is bound by the heparin component of the insoluble granule remnants and degraded by chymase, a granule remnant neutral serine psrotease. The proteolytically modified LDL particles become unstable and fuse on the remnant surface, after which the macrocomplex is phagocytozed and degraded by the macrophage with the subsequent formation of a foam cell, a hallmark of an early atherosclerotic lesion. High density lipoprotein (HDL), being responsible for the efflux of LDL-derived cholesterol from the macrophage foam cell, is also proteolyzed by mast cell chymase and the high-affinity component of the HDL-dependent cholesterol efflux is so impaired. As a result, the balance between cholesterol influx and efflux is disturbed and a cholesterol-filled foam cell is formed. The foam cell may eventually die and so contribute to the formation of an extracellular lipid core, which is a hallmark of an advanced atherosclerotic lesion.

3

Activated mast cells may contribute to plaque erosion and rupture. The number of activated intimal and adventitial mast cells is increased in atherosclerotic plaques. Two types of plaques are shown: (1) a stenotic plaque with a thick fibrous cap and a small necrotic lipid core (left), and (2) a non-stenotic plaque with a thin fibrous cap and a large lipid core (right). The stenotic plaque is prone to erosion and the non-stenotic plaque is prone to rupture. Activated mast cells secrete cytokines and chemokines that regulate innate and acquired immune responses. Mast cells also secrete neutral serine proteases and MMPs that may degrade the components of the pericellular and extracellular matrices, and also the internal elastic lamina. Proteolytic degradation of collagen, elastin and proteoglycan-containing matrices weakens the fibrous cap and renders the plaque susceptible to erosion and rupture. Mast cells, as a source of proangiogenic growth factors and proteases may also induce the formation of neovessels that traverse the medial layer into the intima and weaken the plaque, particularly when they rupture and cause intraplaque haemorrhage. Furthermore, histamine-induced coronary spasm or high shear stress may further precipitate formation of plaque erosions and ruptures. Exposure of the subendothelial thrombogenic tissue at the site of plaque erosion and rupture triggers the formation of an arterial thrombus.