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.
Atherosclerosis is a lipid-driven inflammatory disease of the arterial intima in which the balance of pro-inflammatory and inflammation-resolving mechanisms dictates the final clinical outcome. ...Intimal infiltration and modification of plasma-derived lipoproteins and their uptake mainly by macrophages, with ensuing formation of lipid-filled foam cells, initiate atherosclerotic lesion formation, and deficient efferocytotic removal of apoptotic cells and foam cells sustains lesion progression. Defective efferocytosis, as a sign of inadequate inflammation resolution, leads to accumulation of secondarily necrotic macrophages and foam cells and the formation of an advanced lesion with a necrotic lipid core, indicative of plaque vulnerability. Resolution of inflammation is mediated by specialized pro-resolving lipid mediators derived from omega-3 fatty acids or arachidonic acid and by relevant proteins and signalling gaseous molecules. One of the major effects of inflammation resolution mediators is phenotypic conversion of pro-inflammatory macrophages into macrophages that suppress inflammation and promote healing. In advanced atherosclerotic lesions, the ratio between specialized pro-resolving mediators and pro-inflammatory lipids (in particular leukotrienes) is strikingly low, providing a molecular explanation for the defective inflammation resolution features of these lesions. In this Review, we discuss the mechanisms of the formation of clinically dangerous atherosclerotic lesions and the potential of pro-resolving mediator therapy to inhibit this process.
Chronic inflammation of the arterial wall is a key element in the pathogenesis of atherosclerosis, yet the factors that trigger and sustain the inflammation remain elusive. Inflammasomes are ...cytoplasmic caspase-1-activating protein complexes that promote maturation and secretion of the proinflammatory cytokines interleukin(IL)-1beta and IL-18. The most intensively studied inflammasome, NLRP3 inflammasome, is activated by diverse substances, including crystalline and particulate materials. As cholesterol crystals are abundant in atherosclerotic lesions, and IL-1beta has been linked to atherogenesis, we explored the possibility that cholesterol crystals promote inflammation by activating the inflammasome pathway.
Here we show that human macrophages avidly phagocytose cholesterol crystals and store the ingested cholesterol as cholesteryl esters. Importantly, cholesterol crystals induced dose-dependent secretion of mature IL-1beta from human monocytes and macrophages. The cholesterol crystal-induced secretion of IL-1beta was caspase-1-dependent, suggesting the involvement of an inflammasome-mediated pathway. Silencing of the NLRP3 receptor, the crucial component in NLRP3 inflammasome, completely abolished crystal-induced IL-1beta secretion, thus identifying NLRP3 inflammasome as the cholesterol crystal-responsive element in macrophages. The crystals were shown to induce leakage of the lysosomal protease cathepsin B into the cytoplasm and inhibition of this enzyme reduced cholesterol crystal-induced IL-1beta secretion, suggesting that NLRP3 inflammasome activation occurred via lysosomal destabilization.
The cholesterol crystal-induced inflammasome activation in macrophages may represent an important link between cholesterol metabolism and inflammation in atherosclerotic lesions.
Mast cells are multifarious immune cells with complex roles in tissue homeostasis and disease. They produce a plethora of mediators that play roles in inflammation, angiogenesis, lymphangiogenesis, ...and tissue remodeling. Recent insights into the heterogeneity of cardiac mast cell (CMC) subpopulations have renewed interest in their functional diversity in homeostasis and disease. They are located within the human heart in the myocardium, in atherosclerotic plaques, in the aortic valve, and in close proximity to nerves. Their plasticity enables different and even opposite functions in response to changing tissue contexts. These characteristics render CMCs intriguing, with a dichotomous role in protecting against, or accelerating, cardiovascular diseases. Future work should aim to identify CMC subsets, which could reveal novel therapeutic opportunities for cardiovascular disorders.
Studies with murine mast cells, combining single-cell transcriptomics, imaging, and functional assays, now provide validation of prior observations demonstrating that mast cells form a highly heterogeneous population of immune cells.Mast cells are strategically located in different sections of the human myocardium, coronary arterial wall, and aortic valves. In each location, the mast cells exert organ-specific functions. Recent studies have uncovered mechanisms by which mast cells in these locations may participate both in physiological and pathological processes.Activation of PAR-2 receptors on cardiomyocytes by mast cell tryptase following experimental myocardial infarction can exert a protective effect.Immunologically activated human myocardial mast cells produce both angiogenic (VEGF-A) and lymphangiogenic (VEGF-C) factors that, by inducing the formation of new blood vessels and lymphatic vessels, may provide the myocardial mast cells a contributory role in the prevention and healing of ischemic damage of the myocardium.
Mast cells are potent actors involved in inflammatory reactions in various tissues, including both in the intimal and the adventitial layers of atherosclerotic arteries. In the arterial intima, the ...site of atherogenesis, mast cells are activated to degranulate, and thereby triggered to release an abundance of preformed inflammatory mediators, notably histamine, heparin, neutral proteases and cytokines stored in their cytoplasmic secretory granules. Depending on the stimulus, mast cell activation may also launch prolonged synthesis and secretion of single bioactive molecules, such as cytokines and derivatives of arachidonic acid. The mast cell-derived mediators may impede the functions of different types of cells present in atherosclerotic lesions, and also compromise the structural and functional integrity of the intimal extracellular matrix. In the adventitial layer of atherosclerotic coronary arteries, mast cells locate next to peptidergic sensory nerve fibers, which, by releasing neuropeptides may activate mast cells to release vasoactive compounds capable of triggering local vasoconstriction. The concerted actions of arterial mast cells have the potential to contribute to the initiation and progression of atherosclerosis, and ultimately to destabilization and rupture of an advanced atherosclerotic plaque with ensuing atherothrombotic complications.
Patients with heterozygous familial hypercholesterolemia (HeFH) are at increased risk for COVID-19 cardiovascular complications in the acute phase of the infection. Elevated levels of LDL-C and often ...lipoprotein(a) are present from birth and lead to endothelial dysfunction, which is aggravated by a direct viral attack of the endothelial cells and their exposure to the toxic levels of circulating proinflammatory and prothrombotic mediators during the hyperinflammatory reaction typical of COVID-19.
Evidence to date shows the benefit of lipid-lowering therapy in patients with COVID-19. In HeFH patients who are at much higher cardiovascular risk, the focus should, therefore, be on the effective lowering of LDL-C levels, the root cause of the greater cardiovascular vulnerability to COVID-19 infection in these patients. The ongoing use of statins and other lipid-lowering therapies should be encouraged during the ongoing COVID pandemic to mitigate the risk of cardiovascular complications from COVID-19, particularly in HeFH patients.
Epidemiologic registry data show that the incidence of myocardial infarction is increased in SARS-CoV-2-infected HeFH patients. There is a need to study whether the risk for acute cardiovascular events is increased in the long-term and if there are changes in lipid metabolism after SARS-CoV infection(s) in patients with HeFH.
The emergence and evolution of the complement system and mast cells (MCs) can be traced back to sea urchins and the ascidian Styela plicata, respectively. Acting as a cascade of enzymatic reactions, ...complement is activated through the classical (CP), the alternative (AP), and the lectin pathway (LP) based on the recognized molecules. The system's main biological functions include lysis, opsonization, and recruitment of phagocytes. MCs, beyond their classic role as master cells of allergic reactions, play a role in other settings, as well. Thus, MCs are considered as extrahepatic producers of complement proteins. They express various complement receptors, including those for C3a and C5a. C3a and C5a not only activate the C3aR and C5aR expressing MCs but also act as chemoattractants for MCs derived from different anatomic sites, such as from the bone marrow, human umbilical cord blood, or skin in vitro. Cross talk between MCs and complement is facilitated by the production of complement proteins by MCs and their activation by the MC tryptase. The coordinated activity between MCs and the complement system plays a key role, for example, in a number of allergic, cutaneous, and vascular diseases. At a molecular level, MCs and complement system interactions are based on the production of several complement zymogens by MCs and their activation by MC‐released proteases. Additionally, at a cellular level, MCs act as potent effector cells of complement activation by expressing receptors for C3a and C5a through which their chemoattraction and activation are mediated by anaphylatoxins in a paracrine and autocrine fashion.
Mast cells as effectors in atherosclerosis Bot, Ilze; Shi, Guo-Ping; Kovanen, Petri T
Arteriosclerosis, thrombosis, and vascular biology,
2015-February, Letnik:
35, Številka:
2
Journal Article
Recenzirano
Odprti dostop
The mast cell is a potent immune cell known for its functions in host defense responses and diseases, such as asthma and allergies. In the past years, accumulating evidence established the ...contribution of the mast cell to cardiovascular diseases as well, in particular, by its effects on atherosclerotic plaque progression and destabilization. Through its release not only of mediators, such as the mast cell-specific proteases chymase and tryptase, but also of growth factors, histamine, and chemokines, activated mast cells can have detrimental effects on its immediate surroundings in the vessel wall. This results in matrix degradation, apoptosis, and enhanced recruitment of inflammatory cells, thereby actively contributing to cardiovascular diseases. In this review, we will discuss the current knowledge on mast cell function in cardiovascular diseases and speculate on potential novel therapeutic strategies to prevent acute cardiovascular syndromes via targeting of mast cells.
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