Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199901143400207

Atherosclerosis — An Inflammatory Disease

Although cancer classification has improved over the past 30 years, there has been no general approach for identifying new cancer classes (class discovery) or for assigning tumors to known classes (class prediction). Here, a generic approach to cancer classification based on gene expression monitoring by DNA microarrays is described and applied to human acute leukemias as a test case. A class discovery procedure automatically discovered the distinction between acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) without previous knowledge of these classes. An automatically derived class predictor was able to determine the class of new leukemia cases. The results demonstrate the feasibility of cancer classification based solely on gene expression monitoring and suggest a general strategy for discovering and predicting cancer classes for other types of cancer, independent of previous biological knowledge.

/pdf/molecular-classification-of-cancer-class-discovery-and-class-22p4huwudl.pdf

Molecular classification of cancer: class discovery and class prediction by gene expression monitoring.

Global strategy for asthma management and prevention

Atherosclerosis is an Inflammatory Disease

Abundant data link hypercholesterolaemia to atherogenesis. However, only recently have we appreciated that inflammatory mechanisms couple dyslipidaemia to atheroma formation. Leukocyte recruitment and expression of pro-inflammatory cytokines characterize early atherogenesis, and malfunction of inflammatory mediators mutes atheroma formation in mice. Moreover, inflammatory pathways promote thrombosis, a late and dreaded complication of atherosclerosis responsible for myocardial infarctions and most strokes. The new appreciation of the role of inflammation in atherosclerosis provides a mechanistic framework for understanding the clinical benefits of lipid-lowering therapies. Identifying the triggers for inflammation and unravelling the details of inflammatory pathways may eventually furnish new therapeutic targets.

Inflammation in atherosclerosis

Robbins pathologic basis of disease , Robbins pathologic basis of disease , کتابخانه الکترونیک و دیجیتال - آذرسا

Robbins pathologic basis of disease

Transcription of endothelial-leukocyte adhesion molecule-1 (E-selectin or ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) is induced by the inflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF alpha). The positive regulatory domains required for maximal levels of cytokine induction have been defined in the promoters of all three genes. DNA binding studies reveal a requirement for nuclear factor-kappa B (NF-kappa B) and a small group of other transcriptional activators. The organization of the cytokine-inducible element in the E-selectin promoter is remarkably similar to that of the virus-inducible promoter of the human interferon-beta gene in that both promoters require NF-kappa B, activating transcription factor-2 (ATF-2), and high mobility group protein I(Y) for induction. Based on this structural similarity, a model has been proposed for the cytokine-induced E-selectin enhancer that is similar to the stereospecific complex proposed for the interferon-beta gene promoter. In these models, multiple DNA bending proteins facilitate the assembly of higher order complexes of transcriptional activators that interact as a unit with the basal transcriptional machinery. The assembly of unique enhancer complexes from similar sets of transcriptional factors may provide the specificity required to regulate complex patterns of gene expression and correlate with the distinct patterns of expression of the leukocyte adhesion molecules.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fasebj.9.10.7542214

Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers.

Novel Inhibitors of Cytokine-induced IκBα Phosphorylation and Endothelial Cell Adhesion Molecule Expression Show Anti-inflammatory Effects in Vivo*

CBP (CREB-binding protein) and p300 are versatile coactivators that link transcriptional activators to the basal transcriptional apparatus. In the present study, we identify CBP and p300 as coactivators of the nuclear factor-κB (NF-κB) component p65 (RelA). Consistent with their role as coactivators, both CBP and p300 potentiated p65-activated transcription of E-selectin and VCAM-1–CAT reporter constructs. The N- and C-terminal domains of both CBP/p300 functionally interact with a region of p65 containing the transcriptional activation domain as demonstrated by mammalian two-hybrid assays. Direct physical interactions of CBP/p300 with p65 were demonstrated by glutathione S-transferase fusion protein binding, and coimmunoprecipitation/Western blot studies. The adenovirus E1A 12S protein, which complexes with CBP and p300, inhibited p65-dependent gene expression. Reporter gene expression could be rescued from E1A inhibition by overexpression of CBP or p300. CBP and p300 act as coactivators of p65-driven gene activation and may play an important role in the cytokine-induced expression of various immune and inflammatory genes.

CREB-binding protein/p300 are transcriptional coactivators of p65

Atherosclerosis and its clinical manifestations of heart attack, stroke, and peripheral vascular insufficiency are a major cause of morbidity and mortality among both men and women Multiple risk factors including hypertension, diabetes mellitus, smoking, and lipoprotein disorders are involved in the pathogenesis of this chronic inflammatory disease of arteries

The development of early atherosclerotic lesions can be subdivided into initiation (formation of small fatty streaks), expansion (vertical and lateral growth and coalescence of fatty streaks), and progression to plaques (intimal smooth muscle cell recruitment, collagen deposition, and formation of a fibrous cap) (reviewed in ref1) During the initiation and expansion of fatty streaks, circulating monocytes are recruited to the arterial intima where they are transformed into lipid-engorged macrophage foam cells The arterial endothelium in these regions is activated and expresses inducible leukocyte adhesion molecules and chemokines Production of cytokines and growth factors within lesions may amplify monocyte recruitment, stimulate macrophage proliferation, and induce migration of smooth muscle cells from the media to the intima of the vessel Intimal smooth muscle cells deposit collagen and other ECM proteins, leading to the formation of a fibrous cap Although clinically significant complications of atherosclerosis, such as plaque ulceration, rupture, and thrombosis, occur in established or advanced atherosclerotic plaques, understanding the mechanisms of early lesion formation offers the hope of intervening to delay or prevent lesion progression and complications A select set of transcription factors may be critical in both the initiation and expansion of lesions, as well as in protecting the vessel wall from the formation of atherosclerotic lesions In this overview, we will focus on one transcription factor, NF-κB, whose activation has been linked to the onset of atherosclerosis

NF-κB is composed of members of the Rel family that share a 300 amino acid region, known as the Rel homology domain, which mediates dimerization, nuclear translocation, DNA binding, and interaction with NF-κB inhibitors (reviewed in ref2) Activation of NF-κB is controlled by a family of inhibitors, or IκBs, that bind to NF-κB dimers and mask the nuclear localization sequence of NF-κB, thus retaining the entire complex in the cytoplasm Diverse stimuli activate NF-κB, through the phosphorylation and activation of the IκB kinase (IKK) complex This complex consists of IKK-α and IKK-β heterodimers, a number of IKK-γ subunits, and possibly other components that have less certain significance The activated IKK complex specifically phosphorylates the IκBs, which are then rapidly polyubiquitinated, targeting them for degradation by the proteosome Following release from the inhibitor, NF-κB dimers translocate from the cytoplasm to the nucleus, where they bind target genes and stimulate transcription (Figure ​(Figure1)1) NF-κB activates a variety of target genes relevant to the pathophysiology of the vessel wall, including cytokines, chemokines, and leukocyte adhesion molecules, as well as genes that regulate cell proliferation and mediate cell survival NF-κB also activates the IκBα gene, thus replenishing the cytoplasmic pool of its own inhibitor Restored expression of IκB-α decreases NF-κB activation and diminishes expression of NF-κB–dependent genes The NF-κB/IκB-α autoregulatory system ensures that the induction of NF-κB is transient and that the activated cell returns to a quiescent state Physiological modulation and pathological activation of the NF-κB system may contribute to the changes in gene expression that occur during atherogenesis



Figure 1

Schematic representation of NF-κB as an integrator in atherogenesis Many of the diverse agents associated with the onset of lesion formation interact with specific receptors Angiotensin II (Ang II), cytokines, advanced glycosylation end products 

/pdf/nf-kb-pivotal-mediator-or-innocent-bystander-in-2rxun42o9g.pdf

Tucker Collins

Papers

Robbins pathologic basis of disease

Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers.

Novel Inhibitors of Cytokine-induced IκBα Phosphorylation and Endothelial Cell Adhesion Molecule Expression Show Anti-inflammatory Effects in Vivo*

CREB-binding protein/p300 are transcriptional coactivators of p65

NF-κB: pivotal mediator or innocent bystander in atherogenesis?