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Vascular Inflammation Proteins

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Vascular Inflammation Proteins

Vascular Inflammation Proteins Background

Atherosclerosis is a chronic disease that begins with the recruitment of monocytes to the coronary artery wall leading to the infiltration of macrophages, development of foam cells and formation of plaque, proliferation of the atherosclerotic lesion, and ultimately plaque rupture and ACS clinical events. The pathogenesis of CAD is complex, involving intricate interactions between the vessel wall and circulating blood cells; however, it is clear that innate immune system-mediated inflammatory responses play a key pathological role in all stages of atherogenesis. Most notably, activation of the transcription factor nuclear factor kappa B (NFκB) through toll-like receptors (TLRs) and its downstream signaling is central to the regulation of inflammation and the pathogenesis and progression of atherosclerosis.

Vascular Inflammation

Vascular inflammation is integral to the development and progression of CAD. In the early stages of atherosclerosis, activation of NF-κB results in endothelial activation and increased expression of key pro-inflammatory cytokines (i.e., interleukin-6 [IL-6] and tumor necrosis factor alpha [TNFα]), chemokines (i.e., monocyte chemoattractant protein-1 [MCP- 1]), and cellular adhesion molecules (CAMs; i.e., intracellular adhesion molecule [ICAM]-1 and vascular cellular adhesion molecule [VCAM]-1) on the endothelium. Cytokines are proinflammatory signaling molecules that drive the inflammatory response, chemokines are chemoattractant cytokines that recruit leukocytes to the vessel wall and CAMs mediate leukocyte adherence to the endothelium. Collectively, these pro-inflammatory mediators facilitate the migration, adherence and infiltration of monocytes into the vessel wall where they differentiate into macrophages and engulf lipoproteins to form foam cells, a key step in the development of the atherosclerotic lesion. Circulating IL-6 promotes the release Creactive protein (hs-CRP) from the liver, initiating a systemic inflammatory response that propagates the vascular inflammatory response. These inflammatory processes also contribute to plaque instability by breaking down the extracellular matrix; ultimately resulting in plaque rupture, formation of a thrombus, occlusion of the vessel, and an ACS clinical event.

Recent studies using preclinical models have demonstrated that inhibition of vascular inflammation may be a viable therapeutic strategy to prevent the development and progression of atherosclerosis. For example, LDL receptor knockout mice lacking the chemokine MCP-1 (Ldlr-/-/MCP-1-/-) develop significantly less atherosclerosis than Ldlr-/- mice wild-type (WT) for MCP-1.10 Similarly, mice deficient in both apolipoprotein E (ApoE-/-) and the CAMs ICAM-1 (ApoE-/-/ICAM-1/-), E-selectin (ApoE-/-/E-selectin-/-), or P-selectin (ApoE-/-/P-selectin-/-) have significantly lower atherosclerotic plaque lesion areas than ApoE-/- littermates.11 Collectively, these data indicate that endothelial activation and the subsequent increase in chemokines and CAMs are integral to the development and progression of CAD, and anti-inflammatory therapeutic strategies that attenuate NF-κB mediated vascular inflammation, may attenuate the development and progression of CAD.

In humans, it has become well-established that circulating biomarkers of systemic and vascular inflammation are predictive of CAD risk, as well as prognosis in patients with established CAD. For example, higher circulating levels of CAMs, including VCAM-1, ICAM- 1 and E-selectin, are predictive of death from cardiovascular causes. Similarly, elevated MCP-1 levels are associated with higher risk of all-cause mortality in patients with established CAD. The role of neutrophils in atherosclerosis has recently become appreciated, leading to the study of neutrophil chemokines including epithelial neutrophil activating protein (ENA)-78 as potential mediators of vascular inflammation in patients with CAD. Genetic variation in ENA-78 has been associated with higher plasma ENA-78 levels and higher rates of all-cause mortality in ACS patients. Collectively, these data demonstrate that biomarkers of vascular inflammation are critical in the pathogenesis and progression of CAD and are valuable phenotypic endpoints in pre-clinical and human studies. Consequently, adjunct therapies that attenuate vascular inflammation have enormous therapeutic potential to prevent the progression of atherosclerosis and improve prognosis in CAD patients.

Vascular Inflammation Signaling Pathways

The transcription factor NFκB plays a key role in regulation of inflammation during ischemic and non-ischemic events. It can be activated through the endotoxin signaling receptor, Toll-like receptor (TLR) or cytokine signaling receptor interleukin- 1 receptor (IL-1R). Both receptors share a homologous cytoplasmic signaling Toll/IL-1R (TIR) domain that when activated initiates a signaling cascade culminating in activation of NFκB and transcription of pro-inflammatory genes. NFκB is in the cytoplasm as a homo or heterodimer. In the cytoplasm NFκB is inactive because it is bound to the inhibitor protein of NFκB (IκB) which masks the nuclear localization signal. Endotoxin, cytokines, and free radicals all activate NFκB. NFκB activation is caused by proteolytic degradation of IκB. IκB kinases phosphorylate IκB and cause it to be ubiquinated and targeted to proteosome for degradation. The nuclear localization signal is exposed on NFκB and it translocates to the nucleus, binds to the target genes and initiates transcription. Activation of NFκB, via TLR4 or IL-1R activation, results in increased inflammation, oxidative stress, and ischemic damage due to increased transcription of a variety of proinflammatory mediators such as cytokines, chemokines, adhesion molecules and pro-inflammatory enzymes, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). These increases in COX-2 and iNOS lead to increased oxidative stress due to the peroxidase activity of COX-2 and peroxinitrite formation during NO production. Oxidative stress is a major contributor to the progression of atherosclerosis.

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