Indomethacin inhibits expansion of experimental aortic aneurysms via inhibition of the cox2 isoform of cyclooxygenase

Miralles, Manuel; Wester, William; Sicard, Gregorio A.; Thompson, Robert W.; Reilly, Jeffrey M.

doi:10.1016/s0741-5214(99)70216-8

Cited by 87 publications

(62 citation statements)

References 30 publications

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“…This is also supported by evidence that treatment with anti-inflammatory agents, such as indomethacin, resulted in inhibition of enlargement of experimental AAA. 33 Thus, we hypothesized that hypertension might accelerate the development of AAA through inflammatory changes, because a large number of articles reported a significant …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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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...

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Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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“…COX enzymes are often described as isolated entities, when in reality their functions are controlled by their environment, the level of substrate available, the expression of individual prostanoid synthase enzymes, and the expression and cellular targets of the prostanoid receptors which mediate their actions. The findings of King et al 21 together with others 1,2,[11][12][13][14][15][16][17] indicate that vascular COX enzymes have multiple and varying roles depending on vascular location and environment. Immunohistochemical analyses of large blood vessels shows us that in healthy states COX-1 produces protective PGI 2 constitutively.…”

Section: See Page 1137mentioning

confidence: 93%

“…20 Furthermore, NSAID use is associated with a reduction in abdominal aortic aneurysm expansion. 16,17 In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology, King et al 21 investigate the roles of COX-1 and COX-2 in a model of abdominal aortic aneurysm. Abdominal aortic aneurysms are caused by local permanent dilation, leading to tissue remodelling, weakening, and the potential of rupture.…”

Section: See Page 1137mentioning

confidence: 99%

COX-2 in Cardiovascular Disease

Bishop‐Bailey

Mitchell

Warner

2006

ATVB

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“…In addition to arterial dilatation, AAAs are characterized by degeneration of the arterial architecture, 6 decreased medial elastin content, 7 disruption or fragmentation of elastic lamellae, 8 presence of matrixdegrading enzymes such as matrix metalloproteinases (MMPs), 9,10 inflammatory infiltration, 10 and often calcification. 11 As a result of its multifactorial pathogenesis, antiin-flammatory agents, 12 proteinase inhibitors (such as tissue inhibitors of metalloproteinases [TIMPs]), and genetic and pharmacological inhibition of MMPs 13 have been tested as potential AAA treatments in experimental animals, but none has yet reached clinical application. Because long-term, adequate control of local inflammation and MMP activities may be difficult to achieve and may be accompanied by adverse side effects, 14 our hypothesis was that stabilization of aortic elastin in aneurysm-prone arterial segments offers potential for the development of safe and effective therapies for AAAs.…”

Section: Clinical Perspective P 1737mentioning

confidence: 99%

Elastin Stabilization for Treatment of Abdominal Aortic Aneurysms

et al. 2007

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Background-Maintaining the integrity of arterial elastin is vital for the prevention of abdominal aortic aneurysm (AAA) development. We hypothesized that in vivo stabilization of aortic elastin with pentagalloyl glucose (PGG), an elastin-binding polyphenol, would interfere with AAA development. Methods and Results-Safety and efficacy of PGG treatment were first tested in vitro using cytotoxicity, elastin stability, and PGG-elastin interaction assays. For in vivo studies, the efficacy of PGG was evaluated within a well-established AAA model in rats on the basis of CaCl 2 -mediated aortic injury. With this model, PGG was delivered periadventitially at 2 separate time points during the course of AAA development; aortic diameter, elastin integrity, and other pathological aspects were monitored and evaluated in PGG-treated aortas compared with saline-treated control aortas. Our results show that a one-time periadventitial delivery of noncytotoxic levels of PGG inhibits elastin degeneration, attenuates aneurysmal expansion, and hinders AAA development in rats without interfering with the pathogenic mechanisms typical of this model, namely inflammation, calcification, and high metalloproteinase activities. PGG binds specifically to arterial elastin and, in doing so, preserves the integrity of elastic lamellae despite the presence of high levels of proteinases derived from inflammatory cells. Conclusions-Periadventitial administration of PGG hinders the development of AAA in a clinically relevant animal model. Stabilization of aortic elastin in aneurysm-prone arterial segments offers great potential toward the development of safe and effective therapies for AAAs.

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Indomethacin inhibits expansion of experimental aortic aneurysms via inhibition of the cox2 isoform of cyclooxygenase

Abstract: Indomethacin attenuates aneurysm growth, and its effects are mediated via inhibition of the cox2 isoform of cyclooxygenase, which decreases PGE2 and MMP-9 synthesis.

Cited by 87 publications

References 30 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

COX-2 in Cardiovascular Disease

Elastin Stabilization for Treatment of Abdominal Aortic Aneurysms

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