Cellular and molecular players in the atherosclerotic plaque progression (original) (raw)
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Atherosclerosis, 1999
The atherosclerotic lesion contains large numbers of macrophages and T lymphocytes. This suggests that a cellular immune response may take place in the lesion, and oxidized lipoproteins, heat shock proteins, and microorganisms have been implied as candidate antigens. However, the effector mechanisms elicited by this response have been largely unclear. We have therefore analyzed endarterectomy specimens by immunohistochemistry and reverse transcription-PCR to detect immune cytokines produced by immunocompetent cells of the advanced human plaque. The pro-inflammatory T cell cytokines, interleukin-2 and interferon-g, were found in a large proportion of plaques (IL-2 in 50% and interferon-g in 30% of plaques by immunohistochemistry and mRNA for both cytokines in 70% of plaques by PCR). In contrast, interleukin-4 and interleukin-5 were rarely observed (both cytokines in 10% of plaques by immunohistochemistry, mRNA for interleukin-4 in 10% and for interleukin-5 in 40% by PCR). This demonstrates the presence of a predominantly pro-inflammatory, Th1-type T cell response in atherosclerosis. This conclusion was further supported by the expression of the pro-inflammatory cytokine, interleukin-1 by plaque macrophages and endothelial cells. In addition, the chemokine interleukin-8 and the macrophage differentiation-stimulating cytokine, granulocytemonocyte colony stimulating factor, were observed in plaque tissues, suggesting that the micro-environment promotes monocyte recruitment and macrophage differentiation. Occasional eosinophils and B cells were, however observed, which is compatible with a microheterogeneity within the lesion. Finally, the anti-inflammatory and fibrogenic cytokines, transforming growth factor-b1-3 and its carrier protein, latent TGF-b binding protein, were found in large amounts in all plaques. Together, these results show that a pro-inflammatory, Th1 type cellular immune response takes place in the atherosclerotic plaque. The balance between pro-inflammatory and anti-inflammatory cytokines may be decisive for the progression of the lesion.
Role of Inflammation in Atherosclerosis
Journal of Nuclear Medicine, 2007
Inflammation plays a major role in all phases of atherosclerosis. Stable plaques are characterized by a chronic inflammatory infiltrate, whereas vulnerable and ruptured plaques are characterized by an ''active'' inflammation involved in the thinning of the fibrous cap, predisposing the plaque to rupture. Although a single vulnerable atherosclerotic plaque rupture may cause the event, there are many other types of plaques, several of which are vulnerable. The existence of multiple types of vulnerable plaques suggests that atherosclerosis is a diffuse inflammatory process. A current challenge is to identify morphologic and molecular markers able to discriminate stable plaques from vulnerable ones, allowing the stratification of patients at high risk for acute cardiovascular and cerebrovascular events before clinical syndromes develop. With that aim in mind, this article summarizes the natural history of atherosclerotic plaques, focusing on molecular mechanisms affecting plaque progression and serum markers correlated with plaque inflammation.
Immune-Mediated Inflammation in Vulnerable Atherosclerotic Plaques
Molecules
Atherosclerosis is a chronic long-lasting vascular disease leading to myocardial infarction and stroke. Vulnerable atherosclerotic (AS) plaques are responsible for these life-threatening clinical endpoints. To more successfully work against atherosclerosis, improvements in early diagnosis and treatment of AS plaque lesions are required. Vulnerable AS plaques are frequently undetectable by conventional imaging because they are non-stenotic. Although blood biomarkers like lipids, C-reactive protein, interleukin-6, troponins, and natriuretic peptides are in pathological ranges, these markers are insufficient in detecting the critical perpetuation of AS anteceding endpoints. Thus, chances to treat the patient in a preventive way are wasted. It is now time to solve this dilemma because clear results indicate a benefit of anti-inflammatory therapy per se without modification of blood lipids (CANTOS Trial, NCT01327846). This fact identifies modulation of immune-mediated inflammation as a n...
Induced macrophage activation in live excised atherosclerotic plaque
Immunobiology
Atherosclerotic plaques are complex tissues containing many different cell types. Macrophages contribute to inflammation, formation of the necrotic core, and plaque rupture. We examined whether macrophages in plaque can be activated and compared this to monolayer cells. The volume of calcium in the plaque was compared to the level of macrophage activation measured by total neopterin output. Carotid plaque samples were cut into 3 mm sections and cultured for up to 96 h. Live sections were stimulated with interferon-γ, phytohaemagglutinin or phorbol 12-myristate 13-acetate. Macrophage activation and oxidative stress were monitored by total neopterin (oxidized and non-oxidized 7,8-dihydroneopterin) and neopterin levels every 24 h for up to 4 d. The calcium content of two plaques was investigated by spectral imaging. Direct stimulation of macrophages in plaque sections with interferon-γ caused a sustained increase in neopterin (p = .037) and total neopterin (p = .003). The addition of p...
Atherosclerosis as Inflammation
Annals of Vascular Surgery, 2005
Atherosclerosis has traditionally been attributed to disordered cholesterol metabolism with associated accumulation of lipid substrate in the arterial wall. It is now believed that systemic and local inflammatory events mediate all phases of plaque development, progression, and degeneration. No longer regarded as a bland, mechanical process, plaque evolution is now best understood as a pitched battle between proinflammatory and anti-inflammatory cellular and molecular elements. Not unlike models of chronic wound healing or ischemia-reperfusion, the biologic state of a plaque at any given time is transient and mutable, reflecting a dynamic balance of numerous local and circulating inflammatory forces. Dreaded complications of the disease such as myocardial infarction and stroke result from acute shifts in this balance in favor of plaque instability and vulnerability over stable states of chronic inflammation. The purpose of this article is (1) to review the inflammatory pathogenesis of atherosclerosis on a molecular basis, (2) describe several of the emerging inflammatory biomarkers currently being investigated with particular interest in their possible roles as direct mediators of vascular disease, and (3) identify several important implications for diagnosis and therapy.
International Journal of Medical Biochemistry
Cellular and molecular mechanisms that underlies the formation of atherosclerotic plaque and plaque rupture-review Atherosclerosis (AS) is the main risk factor for CVD and manifested by lipid accumulation, extracellular matrix protein deposition, and calcification in the intima and media of the large to medium size arteries promoting arterial stiffness and reduction of elasticity. It is initiated by endothelium activation and, followed by a cascade of events (accumulation of lipids, fibrous elements, and calcification), triggers the vessel narrowing and activation of inflammatory pathways. This review focuses on the different stages of AS development, ranging from endothelial dysfunction to plaque rupture and the role of genetic abnormalities in AS development. In addition, the correlation of monocyte recruitment and atherogenesis, cytokine involvement with the role of phagocytosis in AS, fundamental signaling pathways in multiple stages of AS, and genetics of AS and the molecular mechanisms of plaque rupture and cap formation are covered here to provide a global view of the disease.
Immunological aspects of atherosclerosis
Physiological research / Academia Scientiarum Bohemoslovaca, 2014
Atherosclerosis is a degenerative inflammatory disease of the vascular wall, which is characterized by the formation of atherosclerotic plaques that contain lipids, activated smooth muscle cells, immune cells, foam cells, a necrotic core and calcified sites. In atherosclerosis pathology, monocytes and macrophages play the most important role by accumulating redundant LDL particles in their oxidized form and producing proinflammatory cytokines. Atherosclerotic plaque macrophages reveal distinct phenotypes that are distinguished into M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages. Numerous environmental signals (cytokines, microbial cell molecules) that are received by macrophages drive their polarization, but it must be determined whether this classification reflects different macrophage subtypes or plasticity and phenotypic tissue changes, but the balance between subsets is crucial. M1 macrophages are dominant in symptomatic atherosclerotic plaques, while M2 macrophage...
Atherosclerotic Plaque Stability—What Determines the Fate of a Plaque?
Progress in Cardiovascular Diseases, 2008
Although the understanding of the underlying pathology of atherosclerosis has improved in recent years, the disease is still the main cause of death globally. Current evidence has implicated the role of inflammation in atherogenesis and plaque destabilization. Thus, inflammatory cytokines may attenuate interstitial collagen synthesis, increase matrix degradation, and promote apoptosis in several atheroma-associated cell types, and all these cellular events may enhance plaque vulnerability. Several cell types found within the lesion (ie, monocyte/macrophages, T cells, mast cells, platelets) contribute to this immune-mediated plaque destabilization, and a better understanding of these processes is a prerequisite for the development of new treatment strategies in these individuals. Such knowledge could also facilitate a better identification of high-risk individuals. In the present study, these issues will be discussed in more detail, particularly focusing on the interactions between matrix degradation, apoptotic, and inflammatory processes in plaque destabilization.