Pathogenesis of Acquired Aneurysms of the Abdominal Aorta

Anidjar, Samy; Kieffer, Édouard

doi:10.1007/bf02000279

Cited by 43 publications

(18 citation statements)

References 101 publications

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“…30 Because human aneurysmal tissues are characterized by destructive remodeling of the elastic media and outer aortic wall, recent investigations have emphasized disease mechanisms involving chronic aortic wall inflammation and the progressive degradation of fibrillar matrix proteins. [31][32][33] The dissolution of elastic fibers requires the presence of specific proteinases, and several elastolytic MMP are thought to contribute to aneurysm development, including MMP-2 and MMP-9. 5,34,35 MMP-9 has attracted particular interest because it is the most abundant elastolytic proteinase secreted by human AAA tissue explants in vitro and is actively expressed by aneurysm-infiltrating macrophages located at the site of tissue damage in situ.…”

Section: Discussionmentioning

confidence: 99%

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

Aoki²,

Miyake³

et al. 2004

Circulation

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Background-Two phenomena, inflammation and matrix degradation, contribute to the progression of abdominal aortic aneurysm (AAA). Importantly, the inflammation is regulated by the transcription factor nuclear factor (NF)-B, whereas the destruction and degradation of elastin fibers by matrix metalloproteinases (MMP) are regulated by ets. Thus, we developed a novel strategy to treat AAA by simultaneous inhibition of both NF-B and ets by using chimeric decoy oligodeoxynucleotides (ODN). Methods and Results-AAA was induced in rats by transient aortic perfusion with elastase, whereas transfection of decoy ODN was performed by wrapping a delivery sheet containing decoy ODN around the aorta. Gel-mobility shift assay at 7 days after treatment demonstrated that both NF-B and ets binding activity were simultaneously inhibited by chimeric decoy ODN. Transfection of chimeric decoy ODN resulted in significant inhibition of the progression of AAA such as aneurysmal dilation at 4 weeks after treatment as compared with control, accompanied by a reduction of MMP expression. Moreover, the destruction of elastin fibers was inhibited in the aorta transfected with chimeric decoy ODN. Importantly, transfection of chimeric decoy ODN demonstrated potent inhibition of aneurysmal dilatation compared with NF-B decoy ODN alone, whereas scrambled decoy ODN had no effects. Interestingly, the migration of macrophages was significantly inhibited by chimeric decoy ODN. Conclusions-We

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Section: Discussionmentioning

confidence: 99%

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

Aoki²,

Miyake³

et al. 2004

Circulation

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“…22 Although elective surgical repair is an effective approach to prevent deaths from AAA rupture, there is a conspicuous absence of alternative therapeutic strategies for this disease. 31 As human aneurysm tissues are characterized by destructive remodeling of the elastic media and outer aortic wall, recent investigations have emphasized disease mechanisms involving chronic aortic wall inflammation and the progressive degradation of fibrillar matrix proteins. [31][32][33] The dissolution of elastic fibers requires the presence of specific proteinases, and several elastolytic MMPs such as MMP-2, MMP-9, MMP-12 and MT1-MMP are thought to contribute to aneurysm development.…”

Section: Discussionmentioning

confidence: 99%

“…31 As human aneurysm tissues are characterized by destructive remodeling of the elastic media and outer aortic wall, recent investigations have emphasized disease mechanisms involving chronic aortic wall inflammation and the progressive degradation of fibrillar matrix proteins. [31][32][33] The dissolution of elastic fibers requires the presence of specific proteinases, and several elastolytic MMPs such as MMP-2, MMP-9, MMP-12 and MT1-MMP are thought to contribute to aneurysm development. 16,17,27,[34][35][36][37][38][39][40][41] MMP-9 has attracted particular interest, because it is the most abundant elastolytic proteinase secreted by human AAA tissue explants in vitro and is actively expressed by aneurysm-infiltrating macrophages located at the site of tissue damage in situ.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ets, an essential transcription factor for angiogenesis, to prevent the development of abdominal aortic aneurysm in a rat model

et al. 2005

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The pathophysiology of abdominal aortic aneurysms (AAA) is considered to be complicated. As matrix degradation contributes to the progression of AAA, the destruction and degradation of elastin fibers caused by an increase in matrix metalloproteinases (MMPs) plays a pivotal role in the development of AAA. Although ets, an essential transcription factor for angiogenesis, regulates MMPs, the role of ets in the development of AAA has not yet been clarified. Thus, we evaluated the role of ets in a rat AAA model using a decoy strategy. Transfection of ODN into AAA was performed by transient aortic perfusion of elastase and by wrapping the AAA in a delivery sheet containing decoy ODN. The inhibitory effect of ets decoy ODN on ets binding activity was confirmed by gel mobility shift assay. MMPs expression was decreased in the aorta transfected with ets decoy ODN as compared to scrambled decoy ODN. Also, ultrasound study demonstrated that elastase-induced aneurismal dilation was significantly suppressed by transfection of ets decoy ODN at 4 weeks after treatment as compared to scrambled decoy ODN. Moreover, the destruction of elastin fibers was inhibited in the aorta transfected with ets decoy ODN, accompanied by a reduction of MMPs expression. An inhibitory effect of decoy ODN on MMP expression was confirmed by ex vivo experiments showing that transfection of decoy ODN into an organ culture of human aorta resulted in significant inhibition of the secretion of both MMP-1 and MMP-9. Here, we demonstrated that ets may play a pivotal role in the progression of AAA through the activation of MMPs in a rat model. Ets might be a potential target to develop pharmacotherapy/gene therapy to treat AAA through the inhibition of MMPs.

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“…Early studies focused on prevalence and natural history, attempting to define risk profiles for developing aneurysms and to determine whether additional factors might precipitate rupture. 1,3,14,15 The association of some aneurysms with connective tissue disorders led to genetic evaluations of families with multiple members affected and to the search for culprit genes. 1,2,16,17 Experiments have sought to identify enzymes in the aorta that might break down collagen and elastin, which compose major structural elements of the vessel wall.…”

Section: Discussionmentioning

confidence: 99%

Death of Smooth Muscle Cells and Expression of Mediators of Apoptosis by T Lymphocytes in Human Abdominal Aortic Aneurysms

et al. 1999

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Background-Thinning of the tunica media and rarefaction of smooth muscle cells (SMCs) characterize aneurysmal aortas. Apoptosis determines the cellularity and morphogenesis of tissue. Macrophages and T lymphocytes infiltrate the wall of abdominal aortic aneurysms (AAAs) and produce death-promoting proteins (perforin, Fas, and FasL). This study investigated whether apoptosis occurs in association with the expression of these proteins. Methods and Results-We examined signs of apoptosis and expression of death-promoting mediators in segments of AAAs from patients undergoing elective repair (nϭ20). Anti-␣-actin immunostaining showed a reduced number of SMCs in AAAs. In situ terminal transferase-mediated dUTP nick end-labeling (TUNEL) showed higher levels of DNA fragmentation in AAAs than in controls (nϭ5). The AAA walls contained more cells bearing markers of apoptosis than normal aorta (PϽ0.05, Student's t test). Double immunostaining identified SMCs and macrophages as the principal cell types displaying fragmented DNA. Immunohistochemistry revealed that AAAs but not normal aorta contained CD4

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Pathogenesis of Acquired Aneurysms of the Abdominal Aorta

Cited by 43 publications

References 101 publications

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

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

Inhibition of ets, an essential transcription factor for angiogenesis, to prevent the development of abdominal aortic aneurysm in a rat model

Death of Smooth Muscle Cells and Expression of Mediators of Apoptosis by T Lymphocytes in Human Abdominal Aortic Aneurysms

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