Inhibition of Experimental Abdominal Aortic Aneurysm in the Rat by Use of Decoy Oligodeoxynucleotides Suppressing Activity of Nuclear Factor κB and ets Transcription Factors

Nakashima, Hideki; Aoki, Motokuni; Miyake, Takashi; Kawasaki, Tomio; Iwai, Masahiro; Jo, Nobuo; Oishi, Masako; Kataoka, Kazusaburo; Ohgi, Shigetsugu; Ogihara, Toshio; Kaneda, Yasufumi; Morishita, Ryuichi

doi:10.1161/01.cir.0000105725.61763.a2

Cited by 97 publications

(86 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…46,47 Consistently, we reported previously that ets was induced in experimental AAA, followed by overproduction of MMPs. 19 Interestingly, the present study indicated that high blood pressure significantly upregulated both NFB and ets in a rat AAA model.…”

Section: Shiraya Et Al Hypertension Accelerated Abdominal Aortic Aneumentioning

confidence: 45%

“…To confirm this hypothesis, we used chimeric decoy ODN, because our previous article demonstrated a suppressive effect of decoy ODN on activation of both NFB and ets, 19,23,24 and observed that in vivo transfection of chimeric decoy ODN using a delivery sheet significantly suppressed the upregulation of NFB and ets induced by elastase. 19 First, we used an ex vivo organ culture system of human vascular tissue from aneurysms and examined the effect of chimeric decoy ODN on the expression of MMP-1 and MMP-9, because MMP-1 and MMP-9 are considered to play a pivotal role in the pathogenesis in human AAA. MMP-1, as well as MMP-9, was readily detected in the conditioned medium from the organ culture system.…”

Section: Prevention Of Development Of Aaa By Chimeric Decoy Odn In Hymentioning

confidence: 99%

“…These data are consistent with a previous report that chimeric decoy ODN inhibited a broad spectrum of MMPs and the migration of macrophages, leading to the prevention of AAA in a normotensive AAA model. 19 Suppression of AAA by chimeric decoy ODN could be mediated by 3 pathways: (1) direct inhibition of MMP gene expression driven by either the NFB or ets binding site, (2) indirect inhibition of MMP secretion, and (3) inhibition of migration of macrophages, which secrete MMPs.…”

Section: Shiraya Et Al Hypertension Accelerated Abdominal Aortic Aneumentioning

confidence: 99%

See 2 more Smart Citations

Hypertension Accelerated Experimental Abdominal Aortic Aneurysm Through Upregulation of Nuclear Factor κB and Ets

et al. 2006

Self Cite

View full text Add to dashboard Cite

Abstract-In this study, we focused on the effect of hypertension on the transcription factors nuclear factor B (NFB) and ets in the mechanisms of abdominal aortic aneurysm (AAA), and we investigated how hypertension affects the progression of AAA. AAA was produced by elastase perfusion in hypertensive rats and normotensive rats. The size of AAA rapidly increased in hypertensive rats as compared with normotensive rats. Western blot analysis demonstrated that the expression of matrix metalloproteinase (MMP)-2, -3 , -9, and -12, as well as intercellular adhesion molecule, was increased in hypertensive AAA rats, accompanied by upregulation of NFB and ets. Moreover, in situ zymography showed that the activity of MMPs was increased in the aorta of a hypertensive AAA model as compared with that in a normotensive AAA model. Interestingly, transfection of chimeric decoy oligodeoxynucleotide (ODN) resulted in significant inhibition of aortic dilatation both in normotensive and hypertensive rats at 4 weeks after transfection. Destruction of elastic fibers was also significantly inhibited by transfection of chimeric decoy ODN in both hypertensive rats and normotensive rats. The expression of MMP-2, -3, -9, and -12, as well as intercellular adhesion molecule, was significantly attenuated by the chimeric decoy ODN, accompanied by inhibition of the migration of macrophages. Also, the effect of chimeric decoy ODN was confirmed in an organ culture. The present study demonstrated that hypertension accelerated the progression of experimental AAA through upregulation of NFB and ets. Inhibition of NFB and ets could be a novel therapeutic strategy to treat AAA in hypertensive patients. bdominal aortic aneurysm (AAA) is a common degenerative condition associated with aging and atherosclerosis. 1 Because the main pathogenesis of AAA is considered to be based on atherosclerosis, patients with aneurysms and atherosclerotic disease share similar risk factors, including male sex, 2 older age, 3 and a lipid profile that includes lower high-density lipoprotein and higher triglyceride and lowdensity lipoprotein concentrations. 4 However, the risk factors for atherosclerosis and AAA are not completely the same, because there are certain pathogenetic, epidemiological, and genetic differences between these 2 diseases. 5,6 Indeed, although hypertension induces sheer stress, oxidative stress, and vascular inflammation followed by atherosclerosis, a consistent relation between blood pressure and the prevalence of AAA has not been demonstrated. 7,8 Hypertension has been reported to be both independently associated with AAA and not associated with AAA. 8,9 Basic phenomena in the pathogenesis of AAA are degradation of extracellular matrix components and loss of structural integrity of the aortic wall. 10 AAA disease typically involves tissue inflammation as seen by the presence of inflammatory cells, which are considered to participate in the immunopathogenesis of AAA leading to destruction of the aortic matrix. 11,12 Recent investigations have emph...

show abstract

Section: Shiraya Et Al Hypertension Accelerated Abdominal Aortic Aneumentioning

confidence: 45%

Section: Prevention Of Development Of Aaa By Chimeric Decoy Odn In Hymentioning

confidence: 99%

Section: Shiraya Et Al Hypertension Accelerated Abdominal Aortic Aneumentioning

confidence: 99%

See 1 more Smart Citation

Hypertension Accelerated Experimental Abdominal Aortic Aneurysm Through Upregulation of Nuclear Factor κB and Ets

et al. 2006

Self Cite

View full text Add to dashboard Cite

show abstract

“…7,26 In addition to the mechanisms above, the functional role of NF-kB that activates MMP-9 expression has been demonstrated in a variety of animal models of abdominal aortic aneurysms. 25,30 A recent paper indicated that activation of NF-kB also appeared at the site of cerebral aneurysm formation. 4 Cerebral aneurysms tend to be formed at the arterial bifurcation by hemodynamic shear stress, and fluid shear stress has been shown to promote the translocation into the nucleus of NF-kB in cultured endothelial cells by activating IkB kinase.…”

Section: Mmpmentioning

confidence: 99%

Suppression of cerebral aneurysm formation in rats by a tumor necrosis factor–α inhibitor

Yokoi¹,

Isono

Saitoh³

et al. 2014

JNS

View full text Add to dashboard Cite

Object Although cerebral aneurysmal subarachnoid hemorrhage is a devastating disease for humans, effective medical treatments have not yet been established. Recent reports have shown that regression of some inflammatory-related mediators has protective effects in experimental cerebral aneurysm models. This study corroborated the effectiveness of tumor necrosis factor–α (TNF-α) inhibitor for experimentally induced cerebral aneurysms in rats. Methods Five-week-old male rats were prepared for induction of cerebral aneurysms and divided into 3 groups, 2 groups administered different concentrations of a TNF-α inhibitor (etanercept), and 1 control group. One month after aneurysm induction, 7-T MRI was performed. The TNF-α inhibitor groups received subcutaneous injection of 25 μg or 2.5 μg of etanercept, and the control group received subcutaneous injection of normal saline every week. The TNF-α inhibitor administrations were started at 1 month after aneurysm induction to evaluate its suppressive effects on preexisting cerebral aneurysms. Arterial circles of Willis were obtained and evaluated 3 months after aneurysm induction. Results Rats administered a TNF-α inhibitor experienced significant increases in media thickness and reductions in aneurysmal size compared with the control group. Immunohistochemical staining showed that treatment with a TNF-α inhibitor suppressed matrix metalloproteinase (MMP)–9 and inducible nitric oxide synthase (iNOS) expression through the luminal surface of the endothelial cell layer, the media and the adventitia at the site of aneurysmal formation, and the anterior cerebral artery–olfactory artery bifurcation. Quantitative polymerase chain reaction also showed suppression of MMP-9 and iNOS by TNF-α inhibitor administration. Conclusions Therapeutic administration of a TNF-α inhibitor significantly reduced the formation of aneurysms in rats. These data also suggest that TNF-α suppression reduced some inflammatory-related mediators that are in the downstream pathway of nuclear factor-κB.

show abstract

“…Likewise, studies have demonstrated that AKT2 deficiency 47 and c-Jun N-terminal kinase activation 38 aggregated AAA development, whereas c-Jun is the major target of c-Jun N-terminal kinase pathway. Besides, nuclear factor-κB also has been reported to regulate MMPs and promote the development of experimental AAA 48 via AP-1 activation. p110δ inactivation may mediate these pathways during vascular injury.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of PI3Kδ Induces Vascular Injury and Promotes Aneurysm Development by Upregulating the AP-1/MMP-12 Pathway in Macrophages

Zheng

Xing

Zeng

et al. 2015

ATVB

View full text Add to dashboard Cite

A neurysms frequently lead to high morbidity and mortality as a result of rupture or dissection without symptoms. 1 Aortic aneurysms, including abdominal aortic aneurysm (AAA), thoracic aneurysms, and carotid aneurysms, are highly common conditions, with AAA being 3 times more prevalent than thoracic aneurysm.2 Although they are typically regarded as being distinct entities, vascular inflammation is a common pathogenic factor in them. 3,4 Pathological features of aneurismal diseases include transmural inflammatory cell infiltration, noticeable breakdown of elastic lamellae, smooth muscle cell loss, endothelial cell death and detachment, neovascularization, calcium deposition, and focal aneurysmal dilation of the vessel wall. 5,6 However, the specific cellular mechanisms that underlie aneurysm formation and progression are poorly understood.Increasing evidence 7,8 points to an important role for innate immune cells in the pathobiology of aneurysms. Monocytes/ macrophages infiltrate the vessel wall and release proteases, including elastase (matrix metalloproteinase-12 ) and metalloproteinases that compromise the integrity of the vascular wall through degradation of the extracellular matrix (ECM). Monocytes/macrophages also secrete inflammatory cytokines in the media and adventitia of aneurysmatic vessels, such as tumor necrosis factor (TNF)-α, interferon-γ, © 2014 American Heart Association, Inc. Objective-An aneurysm is an inflammatory vascular condition. Phosphatidylinositol 3-kinases δ is highly expressed in leukocytes, and play a key role in innate immunity. However, the link between phosphatidylinositol 3-kinases δ and aneurysm development has not yet been elucidated. Approach and Results-Carotid ligation unexpectedly induced characteristic aneurysm formation beneath the ligation point in p110δ D910A/D910A mice (n=25; P<0.001 versus wild-type). Besides, p110δ inactivation exacerbated CaCl 2 -induced abdominal aortic aneurysms development. A reverse transcription polymerase chain reaction microarray revealed significant extracellular matrix components degradation and matrix metalloproteinases (MMPs) upregulation in the abdominal aorta of p110δ D910A/D910A mice. Similarly, the expression of both collagen I and IV was significantly decreased (n=10; P<0.05 versus wild-type) in carotid artery. Western blot assay confirmed that MMP-12 was significantly upregulated in arteries of p110δ D910A/D910A mice (n=10; P<0.01 versus wild-type). In vitro, p110δ inactivation marked increase peritoneal macrophages recruitment and synergistically enhance tumor necrosis factor-α-induced recruitment. A specific phosphatidylinositol 3-kinases δ inhibitor (IC87114) or genetic p110δ inactivation upregulated MMP-12 expression and c-Jun phosphorylation (n=6; P<0.05 versus wild-type macrophages). IC87114 also increased activator protein-1 DNA-binding activity (n=6; P<0.001 versus control) and enhanced the effect of tumor necrosis factor-α on activator protein-1-binding activity (n=5; P<0.01 versus tumor necrosis factor-α treatment ...

show abstract

Inhibition of Experimental Abdominal Aortic Aneurysm in the Rat by Use of Decoy Oligodeoxynucleotides Suppressing Activity of Nuclear Factor κB and ets Transcription Factors

Cited by 97 publications

References 40 publications

Hypertension Accelerated Experimental Abdominal Aortic Aneurysm Through Upregulation of Nuclear Factor κB and Ets

Hypertension Accelerated Experimental Abdominal Aortic Aneurysm Through Upregulation of Nuclear Factor κB and Ets

Suppression of cerebral aneurysm formation in rats by a tumor necrosis factor–α inhibitor

Inactivation of PI3Kδ Induces Vascular Injury and Promotes Aneurysm Development by Upregulating the AP-1/MMP-12 Pathway in Macrophages

Contact Info

Product

Resources

About