General Role Of Inflammation In Atherosclerosis Biology Essay

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Cardiovascular disease has been recently identified as the leading cause of morbidity and mortality worldwide. The main cause underlying CVD is atherosclerosis. Depending on the site affected, it manifests as coronary heart disease, peripheral, carotid and chronic kidney disease. γ

Atherosclerosis, once considered as a disease occurring solely from lipid storage, is nowadays considered a chronic low grade inflammatory condition which affects the vascular wall. It is characterized by the deposition of cholesterol and lipids as well as the infiltration of T-cells and macrophages as a result of endothelial injury response.[1] Oxidative stress is also a key factor in the development of atherosclerosis. Reactive oxygen species (ROS) are capable of not only damaging the cellular components of the vascular wall, but can also affect several redox sensitive transcriptional pathways, shifting the transcriptomic profile to a proatheromatic state. Furthermore, in the sub-endothelial space, ROS oxidize low density lipoproteins (LDL) to oxidized LDL (ox-LDL) which is uptaken by macrophages, subsequently leading to the formation of foam cells. [2] With the progress of time, mature lesions form atherosclerotic plaques, which gradually result to lumen narrowing and occlusion of the vessel. Plaque ulceration or rupture may also occur, leading to acute thrombosis of the lumen. Depending on the site of occlusion this manifests as acute myocardial infarction (AMI) or stroke[3]

The complete mechanism for the formation of atherosclerosis still eludes our grasp, but the theory over atherogenesis continues to evolve as new evidence, underlying its pathophysiology, come to light.

THE ROLE OF REDOX SENSITIVE TRANSCRIPTIONAL PATHWAYS NUCLEAR FACTOR-KAPPA B, ACTIVATOR PROTEIN-1 (AP-1)

Nuclear factor-kappa B (NF-κΒ)

NF-κΒ consists of a family of seven transcriptional factors that all share a Rel homology domain and can homo- or heterodimerize.[4] These are present in almost all mammalian cell types.[5] NF-κΒ can be activated as a cellular response from over 150 stimuli, some including ROS, DNA damage, ultraviolet (UV) radiation, oxLDL, cytokines, bacterial and viral antigens.[5-7] As a gene network expression regulator, NF-κB is involved in several physiological and pathophysiological processes, such as response to stress, cardiovascular growth, cancer, innate/adaptive immunity, cell survival ect. [5, 8] Although all of its subunits are ubiquitously expressed, their action can greatly vary, depending on cell type and induced stimuli, thus creating a vast array of responses. It is reported that activation of NF-κB can lead to a transcription of over 400 genes. Being a redox sensitive transcription factor the redox balance within the cells is a critical element of NF-κΒ activity. [9] While inactive it is bound to its inhibitor (I-κΒα/β) within the cytoplasm.

Concerning atherosclerosis, activation of NF-κΒ following the response to pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-a), interleukin-1 (IL-1) and IL-18, has been identified as a key player for the development of atherosclerosis. genes encoding pro-inflammatory cytokines, chemokines, adhesion molecules, inducible nitric oxide synthase (iNOS), growth factors and enzymes are up-regulated, switching to a more atherogenic profile. [10] These act via two signaling pathways, activating an IκB kinase complex, containing kinases IKKα and IKKβ and a scaffold protein, NF-κΒ essential modifier (NEMO), which plays a regulating role. [6, 11] IkBα/β phosphorylation at NH2-terminal serine residues is then initiated. [12] The phosphorylated product is then ubiquitinated and undergoes degradation by proteasome 26S. This allows for the dimers to unbind from the cytoplasmic complex and translocate to the nucleus. Once inside they bind to specific genes ensuing transcription. [13] Macrophages, endothelial cells (EC) and smooth muscle cells (SMC) of human atherosclerotic lesions were found to have activated NF-κΒ. [14-16]

Activator protein-1

AP-1 is a transcription factor consisting of Jun (c-Jun, Jun-B, Jun-D) and Fos (c-Fos, Fos-B, Fra-1, Fra-2) families of transcriptional factors. These bind to the 12-O-tetradecanoylphorbol-13-acetate (TPA) or cAMP (CRE) elements. [17, 18]. The gene products of this pathway can mitigate or amplify oxidative stress and inflammatory responses [17]. A key point of AP-1 enhanced transcriptional activity is through the phosphorylation of c-Jun by the stress induced family of c-june NH2-terminal kinases (JNK).[19] The JNK pathway regulates a variety of pro-inflammatory genes, which encode cytokines, adhesion molecules, metalloproteinases (MMP's). [20] This regulation is achieved via interaction of JNK and AP-1 pathways, along with other transcription factors. [11]

In atherosclerotic plaques ROS production by cells can have a critical effect on both transcriptional pathways. ROS can oxidize NF-κB subunits and rend them incapable of binding with DNA and subsequently impairing their transcriptional activities. [21] On the other hand, excess in ROS production can lead to increased activation of the JNK/AP-1 pathway, thus creating a new interaction state between these two pathways and greatly affecting pro-inflammatory molecule production. [22]

PRO-INFLAMMATORY CYTOKINES

Cytokines are small cell-signaling protein molecules, which may have autocrine or paracrine action and mediate short range intracellular communication. The cytokine family consists of more than 100 factors, sub-categorized into several smaller clusters, such as interleukins (ILs), interferons (INFs), colony stimulating factors (CSFs), TNFs and chemokines.[23] Cellular sources of cytokines include: vascular cells, leukocytes, platelets and mast cells.[11] Pro-inflammatory cytokines own their proatherogenic potential to several biological effects. At the very first stages of atherosclerosis, endothelial function can be greatly altered by cytokine release. More specifically, INF-γ and TNF-a affect endothelial cadherin- catenin complexes and inhibiting the formation of F-actin stress fibers.[24] In addition TNF-a increases cytosolic Ca2+, resulting in myosin light chain kinase and Ras homolog gene family member A (RhoA) activation and subsequently to endothelial junction disruption.[25] As a result endothelial barrier function is disrupted allowing for easier migration of leukocytes.[26] In addition, cytokine release may result in chemokine and vascular adhesion molecule release, which in turn enhance leukocyte and monocyte migration.[23] Once inside they accelerate foam cell formation from macrophages, through INF-γ mediated up-regulation of SR-PSOX, a scavenger receptor fro ox-LDL and phosphatidylserine.[27]

In later stages of the disease, cytokines like TNF-α, INF-γ and IL-1 may induce macrophage and SMC apoptosis resulting in destabilization of the atheromatic plaque, making it prone to rupturing.[28] Plaque destabilization is further aided by matrix degradation, which is accelerated by pro-inflammatory cytokine release. The latter have a great impact on the expression of MMPs and their inhibitors, tissue inhibitors of metalloproteinases TIMPs, who along with other molecules have a pivotal role in the remodeling of the extracellular matrix.[20] Finally cytokines not only attenuate nitric oxide synthesis, a physiological regulator of vascular tone, but also induce the synthesis of acute phase proteins such as C-reactive protein (CRP), serum amyloid α (SSA), plasminogen and fibrinogen which in turn amplify inflammatory responses.[16]

ADHESION MOLECULES IN ATHEROSCLEROSIS

As aforementioned, cytokine and chemokine release triggers the over-expression of leukocyte adhesion molecules by the ECs. These selectins (P-, E- and L-) and immunoglobin-like molecules. These are composed of intercellular adhesion molecules (ICAMs) ICAM-1, ICAM-2, ICAM-3, vascular cell adhesion molecule 1 (VCAM-1) and platelet endothelial cell adhesion molecule (PECAM-1).[29]

Selectins

Selectins are C-type lectins, sharing a conserved structure and mediate capture, rolling and tethering on the endothelium.[30] L-selectin is expressed by circulating leukocytes and mediates T and B lymphocyte trafficking and homing in areas of chronic inflammation.[31] It is also involved in the capture of flowing leukocytes from rolling ones on the endothelium, also known as secondary capture.[32] P-selectin occurs in atherosclerotic endothelium, but is not found on the non-inflammed one. Ox-LDL and minimally modified LDL (mmLDL) activate P-selectin expression which in turn promotes monocyte adhesion to the endothelium.[33] Studies have also demonstrated that P-selectin is expressed at the very begging of the atherosclerotic process.[34] E-selectin can be found on both cytokine stimulated ECs and on the surface of fibrous, lipid rich atherosclerotic plaques.[35, 36] It is synthesized only under inflammatory conditions and not on healthy non inflamed endothelium.

The mechanisms, under which selectins are downregulated and removed after cell activation, are of great importance, as they are needed to stop they inflammatory process. Inability to do so has detrimental effects in inflammation and on vascular wall integrity. P- and E- selectins are removed through internalization and lysosomal degradation, where L-selectin as well as E- can undergo proteolytic cleavage.[37] As a result soluble forms of these molecules may be found in circulation and may interact with their normal counter-receptors. All selectins interact with sialylated and highly fucosylated carbohydrates, also possessing an affinity for mucin-like glycoproteins. As a result of interaction with their ligands, selectins create weak bonds with the active ECs and leukocytes promoting inflammation and thrombus formation.[29]

IMMUNOGLOBIN-LIKE MOLECULES

Members of the immunoglobin (Ig) family, include glycoprotein membrane receptors with extracellular Ig domains of 70-100 aminoacids, which are present at adhesion sites. Genes of this family give rise to multiple isoforms as a result of alternative splicing.

ICAMs

ICAMs belong to a subfamily of five members, although only ICAM -1, -2 and -3 participate in the inflammatory process. ICAM-1 is regulated by pro-inflammatory stimuli (i.e. oxLDL) and in turn regulates monocyte adhesion to the activated endothelium. ICAM-2 is detected in leukocytes, platelets and the endothelium and inflammatory mediators down-regulate its expression. ICAM-3 is present in leukocytes and ECs, being also the sole ICAM family member found in neutrophils.[29, 33, 38] Common ligands for ICAM molecules are β2 integrins, although each ICAM molecule can bind to multiple ligands by utilizing different binding domains. The strong bonding between ICAMs and integrins allows for firm attachment of inflammatory cells to ECs.[39]

VCAM-1 and PECAM-1

VCAM-1 is primarily expressed on ECs but other cell types (macrophages, dendritic cells, myoblasts) can express it as well. It aids in the recruitment of blood cells, firmly binding them to the activated endothelium. It interacts with integrin α4β1, also referred to as very late antigen 4 (VLA4) by which a change in endothelial cell morphology is initiated, allowing for leukocyte migration. [40] VCAM-1 over-expression is affected by proatherogenic molecules, such as ox-LDL. Proteolytic cleavage of VCAM-1 gives a soluble form (sVCAM-1), which can be a strong independent biomarker, for predicting future fatal cardiovascular events in patients with CAD. [41]

Another member of the Ig family is PECAM-1. It is expressed by hematopoietic, immune and ECs. [42] PECAM-1 molecules can be involved in both homophilic and heterophilic interactions, with the former taking place in adjacent cells and the latter mostly on the same one. [43] PECAM-1 has a key role in leukocyte transmigration which is achieved in multiple ways. In addition, the role of PECAM-1 has been investigated in several disease models, such as ischemia/reperfusion injury, atherosclerosis and other inflammatory diseases. [42]

INNATE AND ADAPTIVE IMMUNITY IN ATHEROSCLEROSIS

Even from the start of the 19th century researchers proposed that there may be a link between atherogenesis and the immune system. [44] As our knowledge about the mechanisms and the processes involved in atherosclerosis evolves, there is nowadays ample evidence that the immune system is a key player in the initiation and progression of atherosclerosis. [45] Firstly immune cells are present in atherosclerotic lesions, resulting in specific pro-inflammatory gene expression. [46] In addition, endothelial dysfunction results not only in loss of antithrombotic ability but in an imbalance of the immune system, with the pro-atheromatic profile prevailing over the anti-atheromatic.[45, 47] Furthermore, most of the aforementioned pro-inflammatory cytokines (ILs, TNFs, INFs) along with anti-inflammatory ones are all secreted from immune cells throughout the atherosclerotic plaques. [48]

Innate Immunity

Innate or non specific immunity is the host's first line of defense against pathogens, in a generic way, lasting briefly compared to the long lasting action of adaptive immunity. It is composed of endothelial or epithelial barriers and circulating cells. Several receptors both responsible for signaling and pattern recognition participate in the innate immune system. [49] A very interesting category is that of the toll-like receptors (TLRs). They are a family of structurally conserved proteins, able to recognize pathogen-associated molecular patterns (PAMPs) on viral and bacterial components and products. [50] Binding of TLRs to their ligands results in the recruitment and activation of adapter proteins to propagate the signal, which in turn activates the NF-κΒ and interferon pathway. [50]

Studies have demonstrated that in atherosclerotic lesions in both humans and mice TLR1, 2 and 4 were expressed mainly in ECs and macrophages. [51] TLR4 was also reported to be up-regulated in patients with coronary disease. [52] A study involving hyperlipidaemic mice with TLR2 deficiency revealed a significant reduction in atherosclerotic lesion severity. [53] A group reported that lack of TLR4 and its adaptor protein MyD-88 attenuates atherosclerotic development.[54]

Dendritic cells (DCs) are considered to act as messengers between the innate and adaptive immune systems. They act as antigen-presenting cells, processing antigen material and presenting it on their surface for other cells to recognize it. [55] Early in atherosclerosis, disturbance in normal endothelial function enhances DC migration and adhesion, resulting in activated DCs. [56] These may create clusters with T cells inside atherosclerotic lesions or may migrate to lymphoid organs and induce T cell activation triggering cytokine release. Reports of DCs present in destabilized, rupture prone plaques indicate their role on plaque destabilization process. [57]

Adaptive immunity

The adaptive or specific immune system is a highly specialized defense mechanism tasked with countering pathogens. Adaptive immunity participates in the development of atherosclerosis in multiple ways: a) via interactions between antigen presenting cells (macrophages, DCs B cells) and naive T cells which create a T cell response, b) T cell cytokine release and c) antibody secretion.

Most T cells involved in the atherogenic process have a Th1 profile producing high amounts of INF-γ, which leads to MMP overexpression, reduced collagen production and thinning of the fibrous cap. [58] In addition, INF-γ activates antigen-presenting cells creating an ever-continuing circle of Th1 response. Also, IL-12 produced by DCs activates STAT 4 and T-box transcription factors expressed in T cells, resulting in overexpression of INF-γ and attenuation of IL-4 and IL-5. [58] Interactions between CD40, expressed by cells of the immune system and mostly in B cells, with its ligand CD40L promote Th1 responses and it has been proposed that inhibition of this pathway reduces atherosclerotic lesion development and shifts to a more plaque stable profile. [59, 60]

Ox-LDL responsible for foam cell formation is also recognized as an antigen by the immune system. Anti-oxLDL antibodies have been detected in patients with peripheral artery disease and CAD, [61] while increased levels of these antibodies may be used to predict the severity of the disease. Human and microbial heat shock protein (HSP) cross-reaction via molecular mimicry may induce TLR-4 production in macrophages, further linking innate and adaptive immunity with the atherosclerotic process. [62]

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