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  • 1
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    Critical role of TNF-α in cerebral aneurysm formation and progression to rupture
    Springer Science and Business Media LLC ; 2014
    In:  Journal of Neuroinflammation Vol. 11, No. 1 ( 2014), p. 77-
    Details
    In: Journal of Neuroinflammation, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2014), p. 77-
    Type of Medium: Online Resource
    ISSN: 1742-2094
    URL: Article
    DOI: 10.1186/1742-2094-11-77
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2014
    detail.hit.zdb_id: 2156455-3
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  • 2
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    The Evolution of Future Directions of Neuroendovascular Therapy: From Clips to Coils to ?
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Neurosurgery Vol. 58 ( 2011-09), p. 42-50
    Details
    In: Neurosurgery, Ovid Technologies (Wolters Kluwer Health), Vol. 58 ( 2011-09), p. 42-50
    Type of Medium: Online Resource
    ISSN: 0148-396X
    URL: Article
    DOI: 10.1227/NEU.0b013e31822785be
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
    detail.hit.zdb_id: 1491894-8
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  • 3
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    Efficacy of endovascular stroke management in elderly patients
    BMJ ; 2016
    In:  Journal of NeuroInterventional Surgery Vol. 8, No. e1 ( 2016-06), p. e7-e8
    Details
    In: Journal of NeuroInterventional Surgery, BMJ, Vol. 8, No. e1 ( 2016-06), p. e7-e8
    Type of Medium: Online Resource
    ISSN: 1759-8478 , 1759-8486
    URL: Article
    DOI: 10.1136/neurintsurg-2012-010525
    Language: English
    Publisher: BMJ
    Publication Date: 2016
    detail.hit.zdb_id: 2506028-4
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  • 4
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    Abstract W P365: Critical Role of Smooth Muscle Cell Phenotypic Modulation in Cerebral Aneurysm Formation and Rupture
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Stroke Vol. 45, No. suppl_1 ( 2014-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 45, No. suppl_1 ( 2014-02)
    Abstract: Objective: Little is known about smooth muscle cell (SMC) phenotypic modulation in the cerebral circulation or pathogenesis of intracranial aneurysms. TNF-α has been associated with aneurysms, but a direct role has not been established. Methods: Cultured cerebral SMC were treated with TNF-α for PCR, western blot, chromatin immune-precipitation (CHIP), and adenovirus promoter transfection. In vivo experiments were carried out in the following models: application of TNF-α to the surface of carotid arteries, cerebral model of hypertension and hemodynamic stress, and cerebral model of aneurysm formation and rupture. The TNF-α inhibitor 3,6’dithiothalidomide (DTH) was synthesized. Results: Cultured cerebral SMC over-expressing myocardin induced expression of key SMC contractile genes (SM-α-actin, SM-22α, SM-MHC), while dominant negative suppressed expression. TNF-α treatment inhibited this contractile phenotype and induced pro-inflammatory genes (MCP-1, MMPs, VCAM-1, IL-1β). TNF-α increased expression of KLF4 and KLF4 siRNA abrogated TNF-α induced phentotypic modulation. These mechanisms were confirmed in vivo following exposure of rat carotid arteries to TNF-α and early in a model of cerebral hypertension and hemodynamic stress prior to cerebral aneurysm formation. Treatment with DTH reversed these pathological vessel wall alterations. TNF-α knock-out mice and DTH pre-treatment decreased the incidence of aneurysm formation and rupture. As compared with sham mice, TNF-α expression was not significantly different in TNF-α knock-out mice or those pre-treated with DTH, but was elevated in unruptured and ruptured aneurysms. Initiation of DTH 7 days after aneurysm induction did not alter aneurysm incidence, but resulted in stabilization and decreased rupture. CHIP assays in vivo and in vitro demonstrated that TNF-α promotes epigenetic changes through KLF4 dependent alterations in promoter regions of myocardin, SMC’s, and inflammatory genes. Conclusion: TNF-α induces phenotypic modulation of cerebral SMC through myocardin and KLF4 regulated pathways. These results demonstrate a novel role for TNF-α in promoting a pro-inflammatory phenotype. These data suggests a critical role of TNF-α in the formation and rupture of aneurysms.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.45.suppl_1.wp365
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 1467823-8
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  • 5
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    Abstract WP87: Endovascular Treatment of Very Small Ruptured Intracranial Aneurysms: Complications, Occlusion Rates and Prediction of Outcome
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Stroke Vol. 44, No. suppl_1 ( 2013-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 44, No. suppl_1 ( 2013-02)
    Abstract: Purpose: In this study we assess predictors of outcome following endovascular treatment of small ruptured intracranial aneurysms (SRA). Methods: Between 2004 and 2011, 91 patients with SRA (≤ 3 mm) were treated at our institution. Multivariate analysis was carried out to assess predictors of endovascular related complications, aneurysm obliteration ( 〉 95%), recanalization, and favorable outcome (Glasgow Outcome Scale 3-5). Results: Endovascular treatment was aborted in 9 of 91 patients (9.9%). Procedure-related complications occurred in 8 of 82 patients (9.8%) of which 5 were transient and 3 were permanent. Three patients (3.7%) undergoing endovascular therapy experienced an intra-procedural aneurysm rupture. Three of 9 patients (33.3%) treated with stent or balloon assisted coiling experienced peri-procedural complications compared to 5 of 73 patients (6.8%) receiving only coils or Onyx (p=0.039). There were no procedural deaths or rehemorrhages. Rates of recanalization and retreatment were 18.2% and 12.7%, respectively. No factors predicted initial occlusion or recanalization. In multivariate analysis pre-treatment factors predictive of favorable outcome included younger age (OR=0.94; 95% CI 0.91-0.99, p=0.017), larger aneurysm size (OR=3.4; 95% CI 1.02-11.11, p=0.045), Hunt and Hess grade (OR=0.38; 95% CI 0.19-0.75, p=0.005), and location (OR=5.12; 95% CI 1.29-20.25, p=0.02). When assessing treatment and post-treatment variables, vasospasm was the only additional covariate predictive of poor outcome (OR=5.90; 95% CI 1.34=25.93, p=0.019). Conclusions: The majority of SRA can be treated with endovascular therapy and limited complications. Overall predictors of outcome for patients undergoing endovascular treatment of SRA include age, aneurysm size, Hunt and Hess grade, location, and post-treatment vasospasm.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.44.suppl_1.AWP87
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 1467823-8
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  • 6
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    Abstract 373: Cigarette Smoke Produces Phenotypic Modulation of Cerebral Vascular Smooth Muscle Cells: Role of KLF4 and Epigenetic Control
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 32, No. suppl_1 ( 2012-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. suppl_1 ( 2012-05)
    Abstract: Objectives: Cigarette smoke is one of the most important environmental factors associated with cerebral aneurysm formation and progression. Cigarette smoke causes phenotypic modulation of Cerebral Vascular Smooth Muscle Cells (VSMCs) which is considered an important underlying mechanism in cerebral aneurysm formation/progression. We studied epigenetic changes caused by Cigarette Smoke Extract (CSE) in VSMC differentiation marker genes. Methods: Rat cerebral VSMCs were treated with CSE at 40 ug/ml (optimal dosage based on preliminary data) dissolved in HEPES buffer (biological activity comparable to soluble components of cigarette smoke in humans) for 2 hours. Cells at 80-90% confluence were fixed with formaldehyde. DNA was sheared using sonication. Chromatin immune-precipitation was performed using following antibodies: 1) anti-KLF4 (Krupple Like Factor 4), 2) anti-HDAC2 (Histone Deacetylase 2), 3) anti-H3K9Ac (Histone 3 Lysine 9 Acetylation), 4) anti-H3K27triMe (Histone 3 Lysine 27 Tri-Methylation) and 5) anti-H4Ac (Histone 4-Acetylation). qPCR was performed with primers specific to CArG containing promoter regions of differentiation marker genes {(alpha-Actin and Myosin Heavy Chain (MHC)} and Myocardin. Results were normalized against input DNA. As part of in vivo experiments Pluronic Gel (40% w/v) containing CSE at 0.8 mg/ml was applied to rat carotid vessels for 6-8 hours. Vessels were harvested and frozen in liquid nitrogen and chromatin immune-precipitation was performed. Results: CSE stimulation promoted a non-differentiated phenotype of cerebral VSMCs. We demonstrated a marked increase in percent enrichment of alpha-actin, MHC and Myocardin promoters with KLF4, HDAC2, and H3K27triMe antibodies and decreased enrichment with H3K9Ac antibody. Although H4Ac antibody showed decreased enrichment at the alpha-Actin promoter, this was not observed for MHC and Myocardin promoters. This was consistent for both in vivo and in vitro studies. Conclusions: We previously demonstrated that CSE decreases expression of cerebral VSMCs marker genes and SRF co-activator, Myocardin and increases expression of transcription factor, KLF4. Further it promotes a pro-inflammatory phenotype. Decreased expression of the above mentioned genes is a result of direct binding of KLF4 to the CArG containing promoter region. Further, KLF4 recruits HDAC2 which deacetylases H3K9 and H4 causing DNA compaction thereby repressing transcription. Our results provide insight into the underlying molecular mechanisms involved in CSE-induced VSMC phenotypic modulation and provide future potential therapeutic targets applicable to cerebral aneurysms.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.32.suppl_1.A373
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
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  • 7
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    Abstract 372: Regulation of Nox1 and Nox2 by Cigarette Smoke in Cerebral Vascular Smooth Muscle Cells: A Role of Oxidative Stress in Cerebral Aneurysm Formation
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 32, No. suppl_1 ( 2012-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. suppl_1 ( 2012-05)
    Abstract: Objectives: Cigarette smoke is one of the most significant environmental risk factor for cerebral aneurysm formation and progression. Factors including inflammation and matrix degradation are considered to be important in aneurysm formation. Reactive Oxygen Species (ROS) play a pathophysiological role in vascular inflammation, proliferation, migration and angiogenesis. Among the major sources of ROS in vascular smooth muscle cells (VSMCs) are NAD(P)H oxidase (Nox). We investigated the role of Cigarette Smoke Extract (CSE) in regulation of Nox1 and Nox2 isoforms in cerebral VSMCs both in vitro and in vivo. Methods: Rat cerebral VSMCs were treated with CSE at 10 and 40 ug/ml for 4 and 24 hours. The level of water soluble components of cigarette smoke and nicotine levels present in the CSE overlap with plasma levels of these constituents in human smokers. RNA was extracted and qPCR was performed. Cerebral VSMCs were transfected with siNox1 and siNox2 for 24 and 72 hours and further incubated with CSE for 24 hours. As part of in vivo studies, Pluronic Gel (40% w/v) containing 0.2-0.8 mg/ml of CSE was applied to the adventitial surface of rat carotid arteries for 24 hours. Vessels were harvested for mRNA quantification. Results: CSE decreased the expression of VSMC marker genes and myocardin, increased expression of KLF4 (a transcription factor) and proinflammatory/matrix remodeling marker genes including MMPs, VCAM1 and MCP1. In addition CSE increased the expression of both Nox1 and Nox2 at 4 and 24 hours but was more significant at 4h. Preliminary studies with siNox1 and siNox2 decreased the expression of KLF4, and reversed inflammatory markers gene expression caused by CSE stimulation. siNox1 increased the expression of marker genes including alpha-Actin and 22-alpha. Expression of Nox1 and Nox2 was markedly increased following in vivo application of pluronic gel. Conclusions: These findings indicate that cerebral VSMCs contain Nox1 and Nox2, are potently regulated by CSE and play an important role in NAD(P)H oxidase driven ROS production. CSE induces marked phenotypic modulation of vertebral VSMC while concomitantly increasing expression of Nox1 and Nox2. Furthermore, alteration of Nox expression abrogates aspects of CSE induced VSMC phenotypic modulation. These molecular changes implicate oxidative stress in vascular pathology underlying cerebral aneurysms and may provide a potential target for future therapeutic strategies.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.32.suppl_1.A372
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
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  • 8
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    Abstract 112: Cigarette Smoke Directly Produces a Pro-inflammatory/matrix remodeling Phenotype in Cerebral Vascular Smooth Muscle Cells via KLF4: A Potential Mechanism for Cerebral Aneurysm Pathogenesis
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Stroke Vol. 43, No. suppl_1 ( 2012-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 43, No. suppl_1 ( 2012-02)
    Abstract: Cigarette smoke is one of the most significant environmental risk factor for cerebral aneurysm formation. Inflammation, matrix degradation and vascular smooth muscle cell phenotypic modulation are thought to be important in aneurysm pathology yet molecular pathogenic mechanisms are unknown. We investigated the role of cigarette smoke in producing phenotypic modulation and inflammation in cerebral vascular smooth muscle cells (VSMCs) focusing on a potential pivotal role of the transcription factor, KLF4. Methods: Rat cerebral VSMCs were treated with Cigarette Smoke Extract (CSE) at 4 and 40 ug/ml for 4, 24 and 48 hours. The level of water soluble components of cigarette smoke and nicotine levels present in the CSE overlap with plasma levels of these constituents in human smokers. SMC marker genes (SM-alpha-Actin, 22-alpha and MHC), transcription co-activator, Myocardin, KLF4 and inflammatory/matrix remodeling genes (MMP-2, 3, 9, VCAM-1, MCP-1, and iNOS) were measured using qPCR. siRNA against KLF4 and non-specific siGFP were transfected in cultured VSMCs to examine a potential critical role for KFL4 in this process. As part of in vivo experiments, Pluronic Gel (40% w/v) containing 0.2 - 0.8 mg/ml CSE was applied to the adventitial surface of rat carotid arteries for 24-48 hours. Results: CSE significantly induced KLF4 expression at 4 hours (p 〈 0.05 vs. baseline) preceding phenotypic modulation of VSMCs. CSE directly produced marked phenotypic modulation with decreased expression of SMC marker genes and myocardin while markedly increasing expression of inflammatory/matrix remodeling genes (p 〈 0.05 vs. baseline). Strikingly, this profound phenotypic modulation was reversed with siKLF4. Similarly, decreased expression of marker genes and Myocardin with concomitant upregulation of KLF4 and inflammatory/matrix remodeling genes was noted following in vivo pluronic gel application containing CSE. The most notable increase was noted in MMPs, MCP-1, IL-1 and TNF-alpha expression (all p 〈 0.05 vs. control). Conclusions: Cigarette smoke directly produces marked phenotypic modulation of cerebral vascular smooth muscle cells in vitro and in vivo promoting a pro-inflammatory/matrix remodeling phenotype. These effects appear to be mediated via KLF4. Inflammation, accelerated matrix remodeling and VSMC phenotypic modulation are implicated in human cerebral aneurysms. The molecular mechanisms activated by cigarette smoke outlined here may have critical implications for human cerebral aneurysm pathogenesis and may represent important targets for future therapy. Fig: Gene Expression.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.43.suppl_1.A112
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
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  • 9
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    Abstract 108: Transcriptional and Epigenetic Regulation of MCP1 by Tumor Necrosis Factor-a and Cigarette Smoke: Key Mediators in Aneurysm Formation
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Stroke Vol. 44, No. suppl_1 ( 2013-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 44, No. suppl_1 ( 2013-02)
    Abstract: Background: Although the underlying pathophysiology involved in aneurysm formation and progression is unknown, both cigarette smoke and alterations in the inflammatory cascade play a key role. We investigated the role of TNF-α and cigarette smoke extract (CSE) induction of an inflammatory phenotype in cerebral vascular smooth muscle cells (VSMC) through regulation of Monocyte Chemoattrant Protein-1 (MCP-1) and Kruppel Like Factor-4 (KLF4). Methods: Cultured cerebral VSMC from rat Circle of Willis were treated with increasing doses of TNF-α and CSE. siRNA specific to KLF4 was transfected into cells, followed by TNF-α and CSE treatment. In vivo, experiments were performed by applying TNF-α and CSE infused pluronic gel to rat carotid artery adventitial surface. MCP1 activity was measured with qPCR. Aneurysm induction surgery was performed in rats, and mRNA from the Circle of Willis was measured with qPCR. Chromatin Immunoprecipitation (ChIP) was performed both in vitro and in vivo using anti-KLF4, anti-histone deacetylase 2 (HDAC2), and anti-histone 4 acetylation (H4Ac) antibodies. Results: TNF-α and CSE treatment for 24-hours increases the expression of MCP-1 both in vitro and in vivo. Treatment with siKLF4 abrogates this inflammatory phenotype. Similarly, increased expression of TNF-α, KLF4, and MCP-1 was found after aneurysm induction in vivo. TNF-α and CSE initiated KLF4 binding to the MCP-1 promoter region in ChIP assays. This increases H4 acetylation and decreases HDAC2 binding to the promoter region resulting in MCP-1 stimulation. Conclusion: TNF-αand CSE induce an inflammatory phenotype in cerebral VSMC by regulating the expression of MCP-1. KLF4 plays a critical role in this process through binding to the promoter region and induction of epigenetic changes favoring MCP-1 expression. MCP-1 upregulation and subsequent inflammatory cell recruitment is likely a key mechanism in cerebral aneurysm formation and may be an important target for future therapy.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.44.suppl_1.A108
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
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  • 10
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    Abstract 185: Infliximab Suppresses TNF-a Induced Inflammatory Phenotype in Cerebral Vascular Smooth Muscle Cells: Implications for Cerebral Aneurysm Formation
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 33, No. suppl_1 ( 2013-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 33, No. suppl_1 ( 2013-05)
    Abstract: Cerebral Aneurysm rupture results in significant morbidity and mortality. TNFα has been associated with cerebral aneurysms, but potential mechanisms have not been established, and its role in phenotypic modulation is unknown. Therapy targeting TNFα may represent a novel treatment strategy for cerebral aneurysms. Hypothesis Infliximab inhibits TNFα induced phenotypic modulation and upregulation of pro-inflammatory mediators. Methods Cultured cerebral VSMC were incubated with increasing concentrations of TNFα and gene expression measured with qPCR. Cerebral aneurysm induction surgery was performed in rats. Animal were euthanized at 4 wks for qPCR and immunohistochemical analysis of the circle of Willis. Animals undergoing aneurysm induction and Infliximab (5mg/kg) treatment were compared to animals undergoing aneurysm induction alone and untreated controls. Results In vitro experiments demonstrated suppression of differentiation markers and induction of pro-inflammatory genes. In vivo, TNFα mRNA and protein expression was significantly elevated following aneurysm induction compared to untreated controls. Expression of inflammatory markers including chemokines (MCP1 and VCAM1), transcription factors (NF-κB, KLF4), matrix remodeling proteins (MMP-2 & 3), IL-1β and iNOS was also increased. Furthermore, aneurysm induction resulted in phenotypic modulation by decreasing expression of SMC differentiation marker gene SM-α−Actin. Treatment with Infliximab significantly suppressed TNFα expression, inhibited expression of inflammatory markers, and decreased the number of CD68+ cells during aneurysm formation. Infliximab also reversed phenotypic modulation in vascular SMC following aneurysm induction. Conclusions TNFα plays a pivotal role in SMC phenotypic modulation with induction of pro-inflammatory genes and inhibition of SMC differentiation marker genes both in cultured cerebral vascular SMC and in vivo following cerebral aneurysm induction. Infliximab promotes anti-inflammatory effects in cerebral vessels by inhibiting TNFα and suppressing a pro-inflammatory cascade, which has important implications for the mechanisms behind intracranial aneurysm formation and potential therapeutic options.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.33.suppl_1.A185
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 1494427-3
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