Mast Cells as Potential Accelerators of Human Atherosclerosis—From Early to Late Lesions

Abstract

Mast cells are present in atherosclerotic lesions throughout their development. The process of atherogenesis itself is characterized by infiltration and retention of cholesterol-containing blood-derived low-density lipoprotein (LDL) particles in the intimal layer of the arterial wall, where the particles become modified and ingested by macrophages, resulting in the formation of cholesterol-filled foam cells. Provided the blood-derived high-density lipoproteins (HDL) particles are able to efficiently carry cholesterol from the foam cells back to the circulation, the early lesions may stay stable or even disappear. However, the modified LDL particles also trigger a permanent local inflammatory reaction characterized by the presence of activated macrophages, T cells, and mast cells, which drive lesion progression. Then, the HDL particles become modified and unable to remove cholesterol from the foam cells. Ultimately, the aging foam cells die and form a necrotic lipid core. In such advanced lesions, the lipid core is separated from the circulating blood by a collagenous cap, which may become thin and fragile and susceptible to rupture, so causing an acute atherothrombotic event. Regarding the potential contribution of mast cells in the initiation and progression of atherosclerotic lesions, immunohistochemical studies in autopsied human subjects and studies in cell culture systems and in atherosclerotic mouse models have collectively provided evidence that the compounds released by activated mast cells may promote atherogenesis at various steps along the path of lesion development. This review focuses on the presence of activated mast cells in human atherosclerotic lesions. Moreover, some of the molecular mechanisms potentially governing activation and effector functions of mast cells in such lesions are presented and discussed.

Mast Cells: Fascinating but Still Elusive after 140 Years from Their Discovery

“…Systemic mastocytosis is a clonal disease associated with a somatic gain-of-function KIT mutation [56,57,123]. Mast cells, strategically located in different sections of the human heart [51,52] and atherosclerotic plaque [32,33], are involved in different phases of atherosclerosis and myocardial infarction. These cells can be involved in several autoimmune disorders, such as rheumatoid arthritis [37], coeliac disease [94], multiple sclerosis [124], and bullous dermatoses [125].…”

“…Moreover, these cells can be activated by different viral [25,26] and bacterial proteins [27,28] and thereby represent a potentially important cell during microbial infections. Therefore, the spectrum of diseases in which mast cells and their mediators have been implicated has extended to include bacterial, fungal, viral, and helminth infections [26,[29][30][31]; several diseases of the cardiovascular [14,32,33] and gastrointestinal systems [34][35][36]; and the joints [37,38]. Figure 1 schematically summarizes the wide spectrum of pathophysiological conditions in which mast cells and their mediators have been implicated during the last decades.…”

“…The authors speculate that novel strategies aimed to block BTL 2 could contribute to the treatment of allergic disorders [50].It is well established that mast cells are strategically localized in different sections of the human heart, such as the myocardium [51,52], the atherosclerotic plaque [33], and the aortic valve [53]. Kovanen comprehensively reviews the complex role of mast cells throughout the progression of early to late lesions of human atherosclerosis [32]. Immunohistochemical studies in autopsied patients and studies in cell culture systems and in atherosclerotic mouse models have collectively provided evidence that mast cell mediators may promote atherogenesis at various stages of lesion development.Mastocytosis is a hematopoietic neoplasm characterized by abnormal expansion and focal accumulation of clonal mast cells in various organs [54][55][56].…”

“…These locations allow mast cells to act as sentinels for tissue damage and pathogen invasion [4]. Moreover, the association between mast cells and blood vessels [32,52] is optimal to foster the rapid recruitment of immune cells out of the bloodstream and into the inflamed tissues. This process is facilitated by the mast cell production of TNF-α [80][81][82][83][84] and IL-1β [85,86] that activate endothelial cells, the release of vasoactive mediators (i.e., histamine and cysteinyl leukotrienes) [87,88], and chemokines that promote the recruitment of inflammatory and immune cells [24,70,[89][90][91][92].…”

Novel Insight into the in vivo Function of Mast Cell Chymase: Lessons from Knockouts and Inhibitors

“…There is extensive documentation suggesting that chymase can modify lipoproteins (high- and low-density lipoproteins) [108] such that atherosclerotic progression is promoted. In support of this, the genetic ablation of Mcpt4 has been associated with reduced atherosclerotic lesions in apolipoprotein E-deficient mice [109].…”