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Abstract-It is now well established that vascular inflammation is an independent risk factor for the development of atherosclerosis. In otherwise healthy patients, chronic elevations of circulating interleukin-6 or its biomarkers are predictors for increased risk in the development and progression of ischemic heart disease. Although multifactorial in etiology, vascular inflammation produces atherosclerosis by the continuous recruitment of circulating monocytes into the vessel wall and by contributing to an oxidant-rich inflammatory milieu that induces phenotypic changes in resident (noninflammatory) cells. In addition, the renin-angiotensin system (RAS) has important modulatory activities in the atherogenic process. Recent work has shown that angiotensin II (Ang II) has significant proinflammatory actions in the vascular wall, inducing the production of reactive oxygen species, inflammatory cytokines, and adhesion molecules. These latter effects on gene expression are mediated, at least in part, through the cytoplasmic nuclear factor-B transcription factor. Through these actions, Ang II augments vascular inflammation, induces endothelial dysfunction, and, in so doing, enhances the atherogenic process. Our recent studies have defined a molecular mechanism for a biological positive-feedback loop that explains how vascular inflammation can be self-sustaining through upregulation of the vessel wall Ang II tone. Ang II produced locally by the inflamed vessel induces the synthesis and secretion of interleukin-6, a cytokine that induces synthesis of angiotensinogen in the liver through a janus kinase (JAK)/signal transducer and activator of transcription (STAT)-3 pathway. Enhanced angiotensinogen production, in turn, supplies more substrate to the activated vascular RAS, where locally produced Ang II synergizes with oxidized lipid to perpetuate atherosclerotic vascular inflammation. These observations suggest that one mechanism by which RAS antagonists prevent atherosclerosis is by reducing vascular inflammation. Moreover, antagonizing the vascular nuclear factor-B and/or hepatic JAK/STAT pathways may modulate the atherosclerotic process. Key Words: atherosclerosis Ⅲ interleukin-6 Ⅲ angiotensin II Ⅲ angiotensinogen Ⅲ hepatic acute-phase response I t is now widely accepted that atherosclerosis involves a series of coordinated cellular and molecular events characteristic of inflammation. 1 The fatty streak, the first identifiable precursor of the atherosclerotic lesion, is an inflammatory reaction composed of lipid, monocytes, and T lymphocytes formed in response to vascular injury. Not normally resident in the vessel wall, these monocytes and lymphocytes are recruited into the subendothelial space through the combined actions of locally produced chemotactic cytokines and adhesion molecules expressed on the injured endothelial surface. Continuous recruitment of addi- See page 1256tional circulating mononuclear cells into the injured vessel wall, LDL oxidation, and reactive smooth muscle proliferation give rise to the com...

Vascular inflammation contributes to cardiovascular diseases such as aortic aneurysm and dissection. However, the precise inflammatory pathways involved have not been clearly defined. We have shown here that subcutaneous infusion of Ang II, a vasopressor known to promote vascular inflammation, into older C57BL/6J mice induced aortic production of the proinflammatory cytokine IL-6 and the monocyte chemoattractant MCP-1. Production of these factors occurred predominantly in the tunica adventitia, along with macrophage recruitment, adventitial expansion, and development of thoracic and suprarenal aortic dissections. In contrast, a reduced incidence of dissections was observed after Ang II infusion into mice lacking either IL-6 or the MCP-1 receptor CCR2. Further analysis revealed that Ang II induced CCR2 + CD14 hi CD11b hi F4/80 -macrophage accumulation selectively in aortic dissections and not in aortas from Il6 -/-mice. Adoptive transfer of Ccr2 +/+ monocytes into Ccr2 -/-mice resulted in selective monocyte uptake into the ascending and suprarenal aorta in regions of enhanced ROS stress, with restoration of IL-6 secretion and increased incidence of dissection. In vitro, coculture of monocytes and aortic adventitial fibroblasts produced MCP-1-and IL-6-enriched conditioned medium that promoted differentiation of monocytes into macrophages, induced CD14 and CD11b upregulation, and induced MCP-1 and MMP-9 expression. These results suggest that leukocyte-fibroblast interactions in the aortic adventitia potentiate IL-6 production, inducing local monocyte recruitment and activation, thereby promoting MCP-1 secretion, vascular inflammation, ECM remodeling, and aortic destabilization.

Nuclear factor (NF)-kappaB is a family of seven structurally related transcription factors that play a central role in cardiovascular growth, stress response, and inflammation by controlling gene network expression. Although the NF- kappaB subunits are ubiquitously expressed, their actions are regulated in a celltype and stimulus-specific manner, allowing for a diverse spectrum of effects. For example, NF-kappalB is activated by cytokines, reactive oxygen species, bacterial cell wall products, vasopressors, viral infection, and DNA damage. Recent molecular dissection of its mechanisms for activation has shown that NF-kappalB can be induced by the so-called "canonical" and "noncanonical" pathways, leading to distinct patterns in the individual subunits activated and downstream genetic responses produced. The canonical pathway involves activating the IkappalB kinase (IKK) with subsequent phosphorylation-induced proteolysis of the IkappaBalpha inhibitors and consequent nuclear translocation of the Rel A transcriptional activator. Recent work using high-density oligonucleotide arrays have begun to systematically dissect the scope of the gene network under canonical NF-kappaB control and have yielded important insights into biological pathways controlled by it. This pathway controls expression of noncontiguous, functionally discrete groups of genes ("regulons"), whose temporal expression occurs in waves. Moreover, its mode of activation (oscillatory or monophasic) plays an important role in determining the spectrum of target genes expressed. By contrast, the noncanonical NF-kappaB activation pathway involves activating the NF-kappaB inducing kinase (NIK) to stimulate IKKalpha-induced phosphorylation and proteolytic processing of the 100-kDa cytoplasmic NF-kappaB2 precursor. Activated NF-kappaB2 then forms a complex with Rel B and NIK to translocate into the nucleus thereby activating a distinct set of genes. Although the noncanonical pathway has been most clearly linked to control of adaptive immunity, recent intriguing studies have implicated this pathway in viral induced stress response and in the metabolic syndrome. In this way, a single family of transcription factors can respond to diverse stimuli to regulate cardiovascular homeostasis.

Respiratory syncytial virus (RSV) is