Introduction
Atherosclerosis is a chronic inflammatory disease that occurs in the arterial walls and is caused by adaptive and innate immune responses. Inflammation controls the development and destabilization of arterial plaque (Bell et al., 2020). Cells involved in the atherosclerotic process are activated by soluble factors known as cytokines. Different biological effects of proinflammatory cytokines account for their proatherogenic activity (Bell et al., 2020). The paper explores the effects of inflammatory cytokines on the development of atherosclerosis, its impact on endothelial function, and how endothelial dysfunction causes plaque buildup.
Effects of Inflammatory Cytokines on the Development of Atherosclerosis
During the early stages of atherosclerosis, interferon-gamma (IFN- γ) and tumor necrosis factor-alpha (TNF-α) modify the distribution of endothelial-cadherin-catenin complexes and hinder the formation of F-actin stress fibers. TNF-α activates RhoA and myosin light chain kinase and raises cytosolic Ca2+ disrupting the endothelial junctions (Fatkhullina et al., 2017). As a result, the intercellular junctions are restructured, facilitating the transmigration of leukocytes which causes loss of barrier function. In addition, cytokines induce the adhesion and chemokine molecule expression on the vascular endothelium, thus favoring the recruitment, adherence, and migration of monocytes and lymphocytes into the vessel wall. When in the intima, leukocytes are activated permanently by locally generated cytokines, speeding up macrophage transformation into foam cells and improving cell-mediated oxidation (Fatkhullina et al., 2017). IFN- γ encourages the formation of foam cells through the upregulation of SR-PSOX, the scavenger receptor for phosphatidylserine and oxidized low-density lipoprotein (oxLDL), which is involved in the uptake of oxLDL, and subsequent foam cell transformation in macrophages. Proatherogenic cytokines such as interleukin-1β (IL-1β) and IFN- γ interfere with the expression of STP-binding membrane cassette transporter A1. IFN- γ could be a molecular link between lipid metabolism and immune activity (Fatkhullina et al., 2017). When the disease advances, proinflammatory cytokines destabilize atherosclerotic plaques by improving cell apoptosis. Macrophage apoptosis causes the formation of cell debris, which results in the enlargement of the lipid core (Fatkhullina et al., 2017). On the other hand, plaque smooth muscle cell (SMC) makes the fibrous cap thin, favoring its rapture. Various proinflammatory cytokines induce SMC and macrophage apoptosis, mainly associated with IL-1, IFN-γ, and TNF-α, enhancing Fas-Fas ligand killing (Fatkhullina et al., 2017). Therefore, anti-inflammatory and pro-cytokines impact matrix metalloproteinases (MMP) expression and their inhibitors in tissue.
Finally, the antithrombotic EC properties can be deeply altered by cytokines. TNF-α and IL-1 increase tissue procoagulant and suppress the anticoagulant activities. The thrombomodulin-protein C system mediates it by reducing the transcription of protein C receptor genes and thrombomodulin. Proinflammatory cytokines modify the EC fibrinolytic properties, reduce the production of tissue plasminogen activators, and increase the secretion of type I plasminogen activator inhibitors (Fatkhullina et al., 2017). Thus, proinflammatory cytokines might precipitate thrombus formation and enhance the development of acute syndromes.
How Inflammatory Cytokines Impacts Endothelial Function
Inflammation is a protective response of tissue that eliminates causative agents and debris and is closely related to repair. The endothelial functioning can be affected when there is unavailability or decreased production of nitric oxide (NO) (Bai et al., 2020). It can also be affected by the imbalance in the relative contribution of endothelium-derived relaxing and contracting factors, such as endothelin-1 (ET-1), oxidants, and angiotensin (Bai et al., 2020). NO, produced by converting the amino acid L-arginine and L-citrulline by the enzyme NO synthase, is a key, relaxing factor vital in regulating tone and vasomotor function. Therefore, endothelial cells’ lower levels of NO production result in the relaxation of smooth muscle and vasodilation, which are anti-thrombogenic to platelets. Different infections can interfere with the normal function of the endothelial. The causes of the inflammation can be multi-factorial, but it may result from various chronic processes (Bai et al., 2020). After the endothelial cells have undergone inflammatory activation, the increased vascular cell adhesion molecules-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) enhance adherence to monocytes (Bai et al., 2020). In addition, the expression of adhesion molecules is caused by proinflammatory cytokines such as TNF-α and IL-1β by the acute-phase protein, C-creative protein (CRP), and ox-LDL uptake through ox-LDL receptor-1 (LOX-1) interactions (Bai et al., 2020). Therefore, these infections interfere with the normal functioning of the endothelial.
How Endothelial Dysfunction Causes Plaque Buildup
During endothelial dysfunction, the activation of cytokines can take place. The activation increases vessel wall permeability to oxidized lipoproteins and inflammation mediators (Kwaifa et al., 2020). Ultimately, this causes structural damage to the arterial wall, the proliferation of the smooth muscle cells, and finally, the formation of atherosclerotic plaque (Kwaifa et al., 2020). When the cells of the endothelial layer get damaged, plaque formation occurs, which is made up of calcium, cholesterol, fat, and other substances in the blood.
Conclusion
Conclusively, this paper has discussed the effects of inflammatory cytokines on the development of atherosclerosis. For instance, inflammatory cytokines IFN- γ and TNF-α modify the distribution of endothelial-cadherin-catenin complexes and hinder the formation of F-actin stress fibers. In addition, proatherogenic cytokines such as IL-1β and IFN- γ interfere with the expression of STP-binding membrane cassette transporter A1. The impact of inflammatory cytokines on endothelial function has also been explained. Endothelial functioning is affected by the decreased production of NO. It is also affected by the imbalance in the relative contribution of endothelium-derived relaxing and contracting factors, such as endothelin-1 (ET-1), oxidant, and angiotensin. Finally, the paper has explained how endothelial dysfunction causes plaque buildup.
References
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