Abdominal Aortic Aneurysms: Basic Mechanisms and Clinical Implications

Thompson, Robert W.; Geraghty, Patrick J.; Lee, Jason K.

doi:10.1067/msg.2002.121421

Cited by 246 publications

(247 citation statements)

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“…Increased collagen turnover that is not adequately matched by collagen deposition is held responsible for the growth and ultimate rupture of AAA. 1 However, the proteases responsible for the increased collagen turnover have not been identified. Load-bearing collagens within the arterial wall are predominantly type I/III fibrillar collagens that are highly resistant toward proteolysis.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 The hallmark pathology of AAA is a persistent proteolytic imbalance that results in excess matrix destruction and progressive weakening of the arterial wall. A number of matrix metalloproteinases (MMPs) (in particular the gelatinases MMP-2 and -9) 1,3 have been implicated as primary proteolytic culprits in the disease, but it is dubious whether these proteases are directly responsible for the weakening and ultimate failure of the aortic wall. Biomechanical studies invariably show that the mechanical stability of the arterial wall essentially relies on fibrillar collagens in media and adventitia.…”

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confidence: 99%

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Collagen Degradation in the Abdominal Aneurysm

Abdul-Hussien

Soekhoe

Weber

et al. 2007

The American Journal of Pathology

163

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Growth and rupture of abdominal aortic aneurysms (AAAs) result from increased collagen turnover . Collagen turnover critically depends on specific collagenases that cleave the triple helical region of fibrillar collagen. As yet , the collagenases responsible for collagen degradation in AAAs have not been identified. Increased type I collagen degradation products confirmed collagen turnover in AAAs (median values: <1 , 43 , and 108 ng/mg protein in control , growing , and ruptured AAAs , respectively). mRNA and protein analysis identified neutrophil collagenase [matrix metalloproteinase (MMP)-8] and cysteine collagenases cathepsin K , L , and S as the principle collagenases in growing and ruptured AAAs. Except for modestly increased MMP-14 mRNA levels , collagenase expression was similar in growing and ruptured AAAs (anteriorlateral wall). Evaluation of posttranslational regulation of protease activity showed a threefold increase in MMP-8 , a fivefold increase in cathepsins K and L , and a 30-fold increase in cathepsin S activation in growing and ruptured AAAs. The presence of the osteoclastic proton pump indicated optimal conditions for extracellular cysteine protease activity. Protease inhibitor mRNA expression was similar in AAAs and controls, but AAA protein levels of cystatin C, the principle cysteine protease inhibitor, were profoundly reduced (>80%). We found indications that this secondary deficiency relates to cystatin C degradation by (neutrophil-derived) proteases. Abdominal aortic aneurysm (AAA) is a common pathology and a major cause of death because of rupture. 1,2 The hallmark pathology of AAA is a persistent proteolytic imbalance that results in excess matrix destruction and progressive weakening of the arterial wall. A number of matrix metalloproteinases (MMPs) (in particular the gelatinases MMP-2 and -9) 1,3 have been implicated as primary proteolytic culprits in the disease, but it is dubious whether these proteases are directly responsible for the weakening and ultimate failure of the aortic wall. Biomechanical studies invariably show that the mechanical stability of the arterial wall essentially relies on fibrillar collagens in media and adventitia. 4 -6 These structural collagens are highly resistant toward proteolytic degradation, and the only mammalian proteases that have been shown to cleave the native triple helical region of fibrillar collagen are the classic collagenases of the MMP family 7 [ie, MMP-1, -8, and -13 and the membrane type-1 MMP (MT-1 MMP or MMP-14 8 )], as well as selected members of the cysteine protease family (ie, cathepsin K, 9,10 L, 11 and possibly S 12 ).Several reports indicate expression of these collagenases in AAA on an individual basis, but comparative data regarding expression of the collagenases, and their possible relationship to rupture of the aneurysm, 13,14 are not available. Moreover, available studies 15 do not address the critical and complex posttranslational regulation of protease activity that involves controlled secretion of an inactive proenzyme,...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Collagen Degradation in the Abdominal Aneurysm

Abdul-Hussien

Soekhoe

Weber

et al. 2007

The American Journal of Pathology

163

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“…MMP2 and MMP9 have been reported to participate in the development of aneurysms, potentially by translating the inflammatory response into altered vessel wall integrity (9). The MMPs and 5-LO have been implicated together in patients with clinical evidence of plaque instability.…”

Section: Discussionmentioning

confidence: 99%

“…AAAs are caused by pathological changes in the aortic wall that lead to segmental weakening, progressive dilation, and spontaneous rupture (8). Chronic inflammation of the aortic wall and proteinase-mediated degradation of structural matrix proteins are believed to contribute to the development of AAA (9), although the precise molecular mechanisms that underlie vessel wall changes remain poorly understood. Zhao et al (10) recently demonstrated that 5-LO plays a striking role in aortic aneurysm formation in a cholate-induced model.…”

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confidence: 99%

Inhibited Aortic Aneurysm Formation in BLT1-Deficient Mice

Ahluwalia

Lin

Tager

et al. 2007

The Journal of Immunology

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Leukotriene B4 is a proinflammatory lipid mediator generated by the enzymes 5-lipoxygenase and leukotriene A4 hydrolase. Leukotriene B4 signals primarily through its high-affinity G protein-coupled receptor, BLT1, which is highly expressed on specific leukocyte subsets. Recent genetic studies in humans as well as knockout studies in mice have implicated the leukotriene synthesis pathway in several vascular pathologies. In this study, we tested the hypothesis that BLT1 is necessary for abdominal aortic aneurysm (AAA) formation, a major complication of atherosclerotic vascular disease. Chow-fed Apoe−/− and Apoe−/−/Blt1−/− mice were treated with a 4-wk infusion of angiotensin II (1000 ng/min/kg) beginning at 20 wk of age, in a well-established murine AAA model. We found a reduced incidence of AAA formation as well as concordant reductions in the maximum suprarenal/infrarenal diameter and total suprarenal/infrarenal area in the angiotensin II-treated Apoe−/−/Blt1−/− mice as compared with the Apoe−/− controls. Diminished AAA formation in BLT1-deficient mice was associated with significant reductions in mononuclear cell chemoattractants and leukocyte accumulation in the vessel wall, as well as striking reductions in the production of matrix metalloproteinases-2 and -9. Thus, we have shown that BLT1 contributes to the frequency and size of abdominal aortic aneurysms in mice and that BLT1 deletion in turn inhibits proinflammatory circuits and enzymes that modulate vessel wall integrity. These findings extend the role of BLT1 to a critical complication of vascular disease and underscore its potential as a target for intervention in modulating multiple pathologies related to atherosclerosis.

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“…The involved pathophysiological processes mainly include oxidative stress, vascular inflammation, and extracellular matrix degradation (Lopez-Candales et al, 1997;Thompson et al, 1997Thompson et al, , 2002. Apoe / mice infused with angiotensin II (AngII) is the most commonly employed animal model to study the pathogenesis of AAA since it mimics almost all the clinical characteristics of human AAA (Daugherty and Cassis, 2004;Weiss et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Baicalein protects against the development of angiotensin II-induced abdominal aortic aneurysms by blocking JNK and p38 MAPK signaling

Wang

Chen

Yan

et al. 2016

Sci. China Life Sci.

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An abdominal aortic aneurysm (AAA) is a permanent, localized dilatation of the abdominal aorta. In western countries, the morbidity of AAA is approximately 8%. Currently, pharmacotherapies for AAA are limited. Here, we demonstrate that baicalein (BAI), the main component of the Chinese traditional drug "Huang Qin", attenuates the incidence and severity of AAA in Apoe / mice infused with angiotensin II (AngII). Mechanically, BAI treatment decreases AngII-induced reactive oxygen species (ROS) production in the aortic wall. Moreover, BAI inhibits inflammatory cell accumulation in the aortas of mice infused with AngII. It also inhibits AngII-induced activation of matrix metalloproteinase 2 (MMP-2) and MMP-9 to maintain elastin content in vivo. In addition, it blocks AngII cascade by downregulating angiotensin type 1 receptor (AT1R) and inhibiting mitogen-activated protein kinases (MAPKs). Taken together, our findings show that BAI is an effective agent for AAA prevention.

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Abdominal Aortic Aneurysms: Basic Mechanisms and Clinical Implications

Cited by 246 publications

References 300 publications

Collagen Degradation in the Abdominal Aneurysm

Collagen Degradation in the Abdominal Aneurysm

Inhibited Aortic Aneurysm Formation in BLT1-Deficient Mice

Baicalein protects against the development of angiotensin II-induced abdominal aortic aneurysms by blocking JNK and p38 MAPK signaling

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