OBJECTIVE—Coronary artery thrombosis can occur in the absence of plaque rupture because of superficial erosion. Erosion-prone atheromata associate with more neutrophil extracellular traps (NETs) than ...lesions with stable or rupture-prone characteristics. The effects of NETs on endothelial cell (EC) inflammatory and thrombogenic properties remain unknown. We hypothesized that NETs alter EC functions related to erosion-associated thrombosis.
APPROACH AND RESULTS—Exposure of human ECs to NETs increased VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) mRNA and protein expression in a time- and concentration-dependent manner. THP-1 monocytoid cells and primary human monocytes bound more avidly to NET-treated human umbilical vein ECs than to unstimulated cells under flow. Treatment of human ECs with NETs augmented the expression of TF (tissue factor) mRNA, increased EC TF activity, and hastened clotting of recalcified plasma. Anti-TF-neutralizing antibody blocked NET-induced acceleration of clotting by ECs. NETs alone did not exhibit TF activity or acceleration of clotting in cell-free assays. Pretreatment of NETs with anti-interleukin (IL)-1α–neutralizing antibody or IL-1Ra (IL-1 receptor antagonist)—but not with anti-IL-1β–neutralizing antibody or control IgG—blocked NET-induced VCAM-1, ICAM-1, and TF expression. Inhibition of cathepsin G, a serine protease abundant in NETs, also limited the effect of NETs on EC activation. Cathepsin G potentiated the effect of IL-1α on ECs by cleaving the pro-IL-1α precursor and releasing the more potent mature IL-1α form.
CONCLUSIONS—NETs promote EC activation and increased thrombogenicity through concerted action of IL-1α and cathepsin G. Thus, NETs may amplify and propagate EC dysfunction related to thrombosis because of superficial erosion.
RATIONALE:Inflammation drives atherogenesis. Animal and human studies have implicated interleukin-1β (IL-1β) in this disease. Moderate hypoxia, a condition that prevails in the atherosclerotic ...plaque, may conspire with inflammation and contribute to the evolution and complications of atherosclerosis through mechanisms that remain incompletely understood.
OBJECTIVE:This study investigated the links between hypoxia and inflammation by testing the hypothesis that moderate hypoxia modulates IL-1β production in activated human macrophages.
METHODS AND RESULTS:Our results demonstrated that hypoxia enhances pro-IL-1β protein, but not mRNA, expression in lipopolysaccharide-stimulated human macrophages. We show that hypoxia limits the selective targeting of pro-IL-1β to autophagic degradation, thus prolonging its half-life and promoting its intracellular accumulation. Furthermore, hypoxia increased the expression of NLRP3, a limiting factor in NLRP3 inflammasome function, and augmented caspase-1 activation in lipopolysaccharide-primed macrophages. Consequently, hypoxic human macrophages secreted higher amounts of mature IL-1β than did normoxic macrophages after treatment with crystalline cholesterol, an endogenous danger signal that contributes to atherogenesis. In human atherosclerotic plaques, IL-1β localizes predominantly to macrophage-rich regions that express activated caspase-1 and the hypoxia markers hypoxia-inducible factor 1α and hexokinase-2, as assessed by immunohistochemical staining of carotid endarterectomy specimens.
CONCLUSIONS:These results indicate that hypoxia potentiates IL-1β expression in cultured human macrophages and in the context of atheromata, therefore unveiling a novel proinflammatory mechanism that may participate in atherogenesis.
In this work we propose a modified holographic softwall model, analytically solvable, to calculate the masses of lightest scalar glueball and its radial excitations and of higher spin glueball states ...for both even and odd spins. From these results we obtain their respective Regge trajectories, associated with the pomeron for even spins and with the odderon for odd spins. These results are in agreement with those calculated using other approaches.
The present review explores the mechanisms of superficial intimal erosion, a common cause of thrombotic complications of atherosclerosis.
Human coronary artery atheroma that give rise to thrombosis ...because of erosion differ diametrically from those associated with fibrous cap rupture. Eroded lesions characteristically contain few inflammatory cells, abundant extracellular matrix, and neutrophil extracellular traps (NETs). Innate immune mechanisms such as engagement of Toll-like receptor 2 (TLR2) on cultured endothelial cells can impair their viability, attachment, and ability to recover a wound. Hyaluronan fragments may serve as endogenous TLR2 ligands. Mouse experiments demonstrate that flow disturbance in arteries with neointimas tailored to resemble features of human eroded plaques disturbs endothelial cell barrier function, impairs endothelial cell viability, recruits neutrophils, and provokes endothelial cells desquamation, NET formation, and thrombosis in a TLR2-dependent manner.
Mechanisms of erosion have received much less attention than those that provoke plaque rupture. Intensive statin treatment changes the characteristic of plaques that render them less susceptible to rupture. Thus, erosion may contribute importantly to the current residual burden of risk. Understanding the mechanisms of erosion may inform the development and deployment of novel therapies to combat the remaining atherothrombotic risk in the statin era.
RATIONALE:Neutrophils likely contribute to the thrombotic complications of human atheromata. In particular, neutrophil extracellular traps (NETs) could exacerbate local inflammation and amplify and ...propagate arterial intimal injury and thrombosis. PAD4 (peptidyl arginine deiminase 4) participates in NET formation, but an understanding of this enzyme’s role in atherothrombosis remains scant.
OBJECTIVE:This study tested the hypothesis that PAD4 and NETs influence experimental atherogenesis and in processes implicated in superficial erosion, a form of plaque complication we previously associated with NETs.
METHODS AND RESULTS:Bone marrow chimeric Ldlr deficient mice reconstituted with either wild-type or PAD4-deficient cells underwent studies that assessed atheroma formation or procedures designed to probe mechanisms related to superficial erosion. PAD4 deficiency neither retarded fatty streak formation nor reduced plaque size or inflammation in bone marrow chimeric mice that consumed an atherogenic diet. In contrast, either a PAD4 deficiency in bone marrow-derived cells or administration of DNaseI to disrupt NETs decreased the extent of arterial intimal injury in mice with arterial lesions tailored to recapitulate characteristics of human atheroma complicated by erosion.
CONCLUSIONS:These results indicate that PAD4 from bone marrow-derived cells and NETs do not influence chronic experimental atherogenesis, but participate causally in acute thrombotic complications of intimal lesions that recapitulate features of superficial erosion.
Abundant experimental and clinical data support a modulatory role for adiponectin in inflammation, dysmetabolism, and disease. Because the activation of cells involved in innate and adaptive immunity ...contributes to the pathogenesis of diseases such as atherosclerosis and obesity, this study investigated the role of adiponectin in human macrophage polarization and T cell differentiation. Examination of the adiponectin-induced transcriptome in primary human macrophages revealed that adiponectin promotes neither classical (M1) nor alternative (M2) macrophage activation but elicits a pro-inflammatory response that resembles M1 more closely than M2. Addition of adiponectin to polyclonally activated CD4+ T lymphocytes did not affect cell proliferation but induced mRNA expression and protein secretion of interferon (IFN)-γ and interleukin (IL)-6. Adiponectin treatment of CD4+ T cells increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and signal transducer and activation of transcription (STAT) 4 and augmented T-bet expression. Inhibition of p38 with SB203580 abrogated adiponectin-induced IFN-γ production, indicating that adiponectin enhances TH1 differentiation through the activation of the p38-STAT4-T-bet axis. Collectively, our results demonstrate that adiponectin can induce pro-inflammatory functions in isolated macrophages and T cells, concurring with previous observations that adiponectin induces a limited program of inflammatory activation that likely desensitizes these cells to further pro-inflammatory stimuli.
Background: Adiponectin modulates inflammatory diseases and dysmetabolism, conditions associated with immune cell activation.
Results: Adiponectin elicits a pro-inflammatory response in human macrophages and promotes TH1 differentiation of isolated CD4+ T cells.
Conclusion: The limited program of inflammatory activation induced by adiponectin likely desensitizes cells to further pro-inflammatory stimuli.
Significance: Interplay of signals regulated by adiponectin may determine its net effect as an inflammatory modulator.
Inflammation in Atherosclerosis Libby, Peter; Okamoto, Yoshihisa; Rocha, Viviane Z. ...
Circulation Journal,
02/2010, Letnik:
74, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Inflammation drives the formation, progression, and rupture of atherosclerotic plaques. Experimental studies have demonstrated that an inflammatory subset of monocytes/macrophages preferentially ...accumulate in atherosclerotic plaque and produce proinflammatory cytokines. T lymphocytes can contribute to inflammatory processes that promote thrombosis by stimulating production of collagen-degrading proteinases and the potent procoagulant tissue factor. Recent data link obesity, inflammation, and modifiers of atherosclerotic events, a nexus of growing clinical concern given the worldwide increase in the prevalence of obesity. Modulators of inflammation derived from visceral adipose tissue evoke production of acute phase reactants in the liver, implicated in thrombogenesis and clot stability. Additionally, C-reactive protein levels rise with increasing levels of visceral adipose tissue. Adipose tissue in obese mice contains increased numbers of macrophages and T lymphocytes, increased T lymphocyte activation, and increased interferon-γ (IFN-γ) expression. IFN-γ deficiency in mice reduces production of inflammatory cytokines and inflammatory cell accumulation in adipose tissue. Another series of in vitro and in vivo mouse experiments affirmed that adiponectin, an adipocytokine, the plasma levels of which drop with obesity, acts as an endogenous antiinflammatory modulator of both innate and adaptive immunity in atherogenesis. Thus, accumulating experimental evidence supports a key role for inflammation as a link between risk factors for atherosclerosis and the biology that underlies the complications of this disease. The recent JUPITER trial supports the clinical utility of an assessment of inflammatory status in guiding intervention to limit cardiovascular events. Inflammation is thus moving from a theoretical concept to a tool that provides practical clinical utility in risk assessment and targeting of therapy. (Circ J 2010; 74: 213-220)
Targeting interleukin-1 (IL-1) represents a novel therapeutic approach to atherosclerosis. CANTOS demonstrated the benefits of IL-1β neutralization in patients post-myocardial infarction with ...residual inflammatory risk. Yet, some mouse data have shown a prominent role of IL-1α rather than IL-1β in atherosclerosis, or even a deleterious effect of IL-1 on outward arterial remodelling in atherosclerosis-susceptible mice. To shed light on these disparate results, this study investigated the effect of neutralizing IL-1α or/and IL-1β isoforms starting either early in atherogenesis or later in ApoE-/- mice with established atheroma.
The neutralization of IL-1α or of both IL-1 isoforms impaired outward remodelling during early atherogenesis as assessed by micro-computed tomographic and histologic assessment. In contrast, the neutralization of IL-1β did not impair outward remodelling either during early atherogenesis or in mice with established lesions. Interleukin-1β inhibition promoted a slant of blood monocytes towards a less inflammatory state during atherogenesis, reduced the size of established atheromata, and increased plasma levels of IL-10 without limiting outward remodelling of brachiocephalic arteries.
This study established a pivotal role for IL-1α in the remodelling of arteries during early experimental atherogenesis, whereas IL-1β drives inflammation during atherogenesis and the evolution of advanced atheroma in mice.
In this work we use gauge/string dualities and a dynamical model that takes into account dynamical corrections to the metric of the anti de Sitter space due to a quadratic dilaton field and calculate ...the masses of even and odd spin glueball states with P=C=+1, and P=C=−1, respectively. Then we construct the corresponding Regge trajectories which are associated with the pomeron for even states with P=C=+1, and with the odderon for odd states with P=C=−1. We compare our results with those coming from experimental data as well as other models.
In this work we study the electric and magnetic Sachs form factors for proton and neutron by using a deformed gravity/gauge model. We describe holographically baryons as well as gauge bosons which ...are ruled by the parameters kB and kγ, associated with confinement and kinematical energy scales, respectively. Then, we construct the interaction action and calculate the electric and magnetic form factors for the proton and the neutron, and their electromagnetic sizes. The obtained results are compatible with those found in the literature from experimental and theoretical data.
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