NF-κB Is a Key Mediator of Cerebral Aneurysm Formation

Aoki, Tomohiro; Kataoka, Hiroharu; Shimamura, Munehisa; Nakagami, Hironori; Wakayama, Kouji; Moriwaki, Takuya; Ishibashi, Ryota; Nozaki, Kazuhiko; Morishita, Ryuichi; Hashimoto, Nobuo

doi:10.1161/circulationaha.107.728303

Cited by 236 publications

(259 citation statements)

References 32 publications

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“…Rat CAs were induced as previously described 13,14 (Supplementary Figure 1) in which we have repeatedly demonstrated the similarity of this model with human CAs and suitability as a CA model. 11,15,16 Briefly, under the general anesthesia by pentobarbital (50 mg/kg i.p.…”

Section: Materials and Methods Induction Of Experimentally Induced Camentioning

confidence: 96%

Complementary inhibition of cerebral aneurysm formation by eNOS and nNOS

Aoki

Nakagawa

Kataoka

et al. 2011

Laboratory Investigation

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The rupture of cerebral aneurysm (CA) and subsequent subarachnoid hemorrhage can cause fatal results. Recent experimental findings have suggested that the mechanism of CA formation is based on chronic inflammation in arterial walls by hemodynamic force. Endothelial nitric oxide synthase (eNOS) protects arterial walls from vascular inflammation by relieving hemodynamic force through nitric oxide (NO) production. Thus, the expression and protective role of eNOS in CA formation have been investigated in this study. In this study, experimental induced rodent CA models by carotid ligation and systemic hypertension were used. The expression of eNOS was examined in rat CA models and revealed that it was decreased at the site of CA formation. Next, CA was induced in eNOS À/À mice to clarify the role of eNOS in CA formation. In eNOS À/À mice, the incidence of CA formation was similar to that found in wild-type mice. In CA walls of eNOS À/À mice, the expression of neuronal nitric oxide synthase (nNOS) was upregulated compared with that in wild-type mice, suggesting the compensatory effect of nNOS. Hence, eNOS À/À nNOS À/À mice were generated, underwent CA induction and confirmed that eNOS À/À nNOS À/À mice exhibited an increased incidence of CA formation accompanied by accelerated macrophage infiltration. These results suggested that the deficiency of eNOS could be compensated by nNOS upregulation in cerebral arteries and that the eNOS and nNOS complementarily had the protective role in CA formation. The results of this study will provide us with new insight about the mechanisms of CA formation and the functional redundancy between eNOS and nNOS in cerebral arteries.

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Section: Materials and Methods Induction Of Experimentally Induced Camentioning

confidence: 96%

Complementary inhibition of cerebral aneurysm formation by eNOS and nNOS

Aoki

Nakagawa

Kataoka

et al. 2011

Laboratory Investigation

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“…In the present study, we fed rats on a 3‐aminopropionitrile–containing diet, which regulates extracellular matrix organization, to facilitate IA formation in this rodent model, as reported previously 3, 9, 11, 12. Importantly, anagliptin treatment did not affect lysyl oxidase activity in the blood (Figure S2), meaning that the effect of anagliptin on IA growth may not directly associate with the regent 3‐aminopropionitrile, an inhibitor of the catalytic activity of lysyl oxidase.…”

Section: Resultsmentioning

confidence: 99%

“…Although surgical clipping and coiling have become established therapies for IAs, effective noninvasive medical therapies that reduce the risk of aneurysm growth do not exist. Recent studies have revealed that chronic inflammatory responses underlie IA growth 3, 4. In fact, several anti‐inflammatory agents inhibit aneurysms in rodent models,5, 6 yet no clinical trial has conclusively demonstrated the effectiveness of these reagents in humans.…”

Section: Introductionmentioning

confidence: 99%

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

Ikedo

Minami

Kataoka

et al. 2017

JAHA

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BackgroundChronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP‐4 (dipeptidyl peptidase‐4) inhibitors have anti‐inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP‐4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model.Methods and Results IAs were surgically induced in 7‐week‐old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide‐treated RAW264.7 macrophages. In the anagliptin‐treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP‐1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide‐stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, MCP‐1, and IL‐6 (interleukin 6) independent of GLP‐1 (glucagon‐like peptide 1), the key mediator in the antidiabetic effects of DPP‐4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal–regulated kinase 5), which mediates the anti‐inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP‐1 and IL‐6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro.ConclusionsA DPP‐4 inhibitor, anagliptin, prevents the growth of IAs via its anti‐inflammatory effects on macrophages.

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“…This is indicated by the expression of vascular growth factor receptors, proliferation markers, signs of apoptosis and activated intracellular pathways related to growth. [11][12][13] The complement system is a major part of innate immunity, which also regulates the adaptive immune system. Growing evidence points to an important role of comple-ment in injury responses, involving the clearance of tissues from accumulating debris together with phagocytes.…”

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confidence: 99%

Complement system becomes activated by the classical pathway in intracranial aneurysm walls

Tulamo

Frösén

Junnikkala

et al. 2010

Laboratory Investigation

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Inflammation and activation of the complement system in the intracranial aneurysm (IA) wall predispose to IA rupture. We have previously shown that increased C5b-9 accumulation correlates with IA rupture and wall degeneration. To elucidate the underlying mechanisms, we investigated initiators and the pathway of complement activation in unruptured and ruptured IAs. Unruptured and ruptured IA wall samples were studied in parallel sections by immunohistochemical and immunofluorescence stainings for the location and relations of classical and alternative pathway complement components (C1q, C3b/iC3b, C3d, C4b/iC4b; n ¼ 35 and properdin, n ¼ 10), putative complement activators IgG (n ¼ 90), IgM, CRP and OxLDL (n ¼ 10), and complement activation endproduct C5b-9. Classical pathway components were seen in all IAs, and they were located mostly in the extracellular matrix. The early pathway complement components colocalized with each other, but were present in larger areas than C5b-9. The areas positive for complement component accumulation were significantly broader in ruptured than in unruptured IAs. The potential complement activators IgG, IgM, CRP and OxLDL were found mostly in the extracellular matrix and in partial overlap with C5b-9. Lipids were seen in Oil-Red-O staining in colocalization with C5b-9. Complement becomes activated by the classical pathway in the IA wall. The activation appears to be induced by multiple factors, which, in addition to the traditional activators (immunoglobulins, CRP, OxLDL), could involve vascular pressure-induced tissue damage. Despite wide early pathway activation, the terminal pathway is focused on a distinct lipid-rich layer. The profile of the complement components and the association of C5b-9 with lipids in the extracellular matrix indicate a long-term chronic inflammatory process rather than an acute targeted inflammatory reaction. The observed pattern of complement activation may be the consequence of local stress-induced insufficiency of complement regulation in IA walls. KEYWORDS: aneurysm; complement; CRP; immunoglobulin; inflammation; oxidized LDL Saccular intracranial artery aneurysm (IA) rupture causes subarachnoidal hemorrhage (SAH), with up to 50% mortality. 1 However, the mechanisms behind IA development, structural weakening and rupture are poorly understood. In a meta-analysis, 2.3% (range 0.4-6.0%) of various populations were found to harbor IA. 2 Known risk factors for IA rupture and SAH include smoking, hypertension, previous rupture, female gender, excessive alcohol abuse and family history, but these explain only part of the IA disease. 3,4 Inflammation and its key component complement activation precede IA rupture. Inflammatory cell infiltration and deposits of the activation products of the terminal complement pathway can be found in unruptured IAs. 5-9 Immunoglobulins and pro-inflammatory cytokines (eg, TNF-a) have also been detected in human IAs. 8,10 The IA wall undergoes a remodeling process. This is indicated by the expression of vascular growth factor r...

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NF-κB Is a Key Mediator of Cerebral Aneurysm Formation

Cited by 236 publications

References 32 publications

Complementary inhibition of cerebral aneurysm formation by eNOS and nNOS

Complementary inhibition of cerebral aneurysm formation by eNOS and nNOS

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

Complement system becomes activated by the classical pathway in intracranial aneurysm walls

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