Pathogenesis of abdominal aortic aneurysm: an update and look toward the future

Grange, Janet J.; Davis, Valerie A.; Baxter, B. Timothy

doi:10.1016/s0967-2109(97)00018-5

Cited by 80 publications

(62 citation statements)

References 66 publications

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“…This generally occurs at sites where there is atherosclerotic plaque. [1][2][3] Previously, we have demonstrated that proteases, especially urokinase plasminogen activator (uPA) are highly expressed in a mouse model of AAA, 4 and that uPA deficiency decreased the incidence of AAA. 5 Vascular inflammation is a prominent feature of atherosclerotic AAA, [6][7][8] characterized by the infiltration of monocytes/macrophages and lymphocytes into the arterial wall.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of PAI-1 prevents the development of abdominal aortic aneurysm in mice

Hs¹,

Jm²,

P³

et al. 2007

Gene Ther

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Vessel wall inflammation and matrix destruction are critical to abdominal aortic aneurysm (AAA) formation and rupture. We have previously shown that urokinase plasminogen activator (uPA) is highly expressed in experimental AAA and is essential for AAA formation and expansion. In this study, we examined the effects of overexpression of a natural inhibitor of uPA, plasminogen activator inhibitor-1 (PAI-1), on the development of angiotensin (Ang) II-induced AAA in ApoE-deficient (ApoE À/À ) mice. Mice were treated with recombinant adenovirus containing either the human PAI-1 gene (Ad5.CMV.PAI-1) or the luciferase gene (Ad5.CMV.Luc) delivered either locally by intra-adventitial injection or systemically by tail vein injection. Our results show that local delivery of the PAI-1 gene completely prevented AAA formation (0 vs 55.6% in Ad5.CMV.Luc controls, Po0.05). In contrast, systemic delivery of the PAI-1 gene did not affect AAA incidence (78 vs 90% in Ad5.CMV.Luc controls, P ¼ 0.125). Local delivery of the PAI-1 gene 2 weeks after Ang II infusion prevented further expansion of small aneurysms, but had no significant effect on the progression of larger aneurysms. These data suggest that local PAI-1 gene transfer could be used to stabilize small AAA and reduce the rate of expansion and risk of rupture.

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Section: Introductionmentioning

confidence: 99%

Overexpression of PAI-1 prevents the development of abdominal aortic aneurysm in mice

Hs¹,

Jm²,

P³

et al. 2007

Gene Ther

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“…Aneurysms also occur with a familial tendency that suggests a genetically inherited component to the disease (5)(6)(7)(8), but specific gene defects underlying the common forms of AAA have yet to be identified (9,10). Whereas aneurysmal degeneration is thought to arise through mechanisms of vascular wall remodeling distinct from those observed in either aging, atherosclerosis, or hypertension alone, the etiology of AAA remains unresolved (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

“…Tissue remodeling in aneurysms is characterized by destruction of the structural and cellular components of the aortic wall in association with chronic transmural inflammation (11)(12)(13). The most prominent of these features is progressive irreversible degeneration of the elastic media (14-16), a significant finding given the biologic stability of elastin in tissue (17,18).…”

Section: Introductionmentioning

confidence: 99%

Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms.

Curci¹,

Liao²,

Huffman³

et al. 1998

J. Clin. Invest.

435

336

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Elastolytic matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of abdominal aortic aneurysms (AAA), a disorder characterized by chronic aortic wall inflammation and destruction of medial elastin. The purpose of this study was to determine if human macrophage elastase (HME; MMP-12) might participate in this disease. By reverse transcription-polymerase chain reaction, HME mRNA was consistently demonstrated in AAA and atherosclerotic occlusive disease (AOD) tissues (six of six), but in only one of six normal aortas. Immunoreactive proteins corresponding to proHME and two products of extracellular processing were present in seven of seven AAA tissue extracts. Total HME recovered from AAA tissue was sevenfold greater than normal aorta ( P Ͻ 0.001), and the extracted enzyme exhibited activity in vitro. Production of HME was demonstrated in the media of AAA tissues by in situ hybridization and immunohistochemistry, but HME was not detected within the media of normal or AOD specimens. Importantly, immunoreactive HME was specifically localized to residual elastin fragments within the media of AAA tissue, particularly areas adjacent to nondilated normal aorta. In vitro, the fraction of MMP-12 sequestered by insoluble elastin was two-to fivefold greater than other elastases found in AAA tissue. Therefore, HME is prominently expressed by aneurysm-infiltrating macrophages within the degenerating aortic media of AAA, where it is also bound to residual elastic fiber fragments. Because elastin represents a critical component of aortic wall structure and a matrix substrate for metalloelastases, HME may have a direct and singular role in the pathogenesis of aortic aneurysms.

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“…Aortic aneurysms are characterized by weakening, dilation, and occasional rupture of the vessel wall. Development of aneurysms is associated with inflammation, tissue remodeling, and upregulation of matrix-degrading proteinases, and it correlates with atherosclerosis, aging, pulmonary emphysema, and high blood pressure (13,14). Matrix metalloproteinases (MMPs) can degrade a variety of extracellular matrix (ECM) molecules (15), and increased levels of MMP-2 (gelatinase A), MMP-9 (gelatinase B), and MMP-12 (macrophage elastase) have been found in the aneurysmal vessel wall (14,16).…”

mentioning

confidence: 99%