Tumor necrosis factor-α converting enzyme is a key mediator of abdominal aortic aneurysm development.

Tumor necrosis factor (TNF)-α is known to be elevated in plasma and the aorta in abdominal aortic aneurysm (AAA) patients. We sought to clarify the role of TNF-α converting enzyme (Tace), which cleaves the transmembrane precursor of TNF-α, in AAA development. We obtained aortic sample of AAA during surgical operation to assess the histological features and protein expression of human AAA. AAA was induced in mice with temporal systemic deletion of Tace by the inducible Mx-1 Cre transgene (TaceMx1) and in wild-type littermates (CON) by periaortic application of CaCl(2) (AAA/TaceMx1, AAA/CON). Tace expression was increased in human AAA samples as compared with normal aorta. Six weeks postoperatively, aortic diameter in AAA/TaceMx1 was decreased than in AAA/CON in association with attenuated TNF-α expression and extracellular matrix disruption. Increased activities of matrix metalloproteinase (MMP)-9 and MMP-2, numbers of Mac-2-positive macrophages, CD3-positive T lymphocytes and CD31-positive vessels in periaortic tissues, mRNA expression of CD68, monocyte chemotactic protein-1, TNF-α, vascular endothelial growth factor-A, p47 and glutathione peroxidases, and protein expression of phospho-c-Jun N-terminal kinase in AAA were all attenuated by Tace deletion. Protein expression of transforming growth factor (TGF)-β1 was upregulated by Tace deletion in sham-operated mice. TGF-β1 expression was further increased in AAA/TaceMx1. Tace was overexpressed in the aortic wall in human and experimental AAA. Temporal systemic deletion of Tace prevented AAA development in association with attenuating inflammation, oxidative stress, neoangiogenesis and extracellular matrix disruption, suggesting a crucial role of Tace in AAA development.

Kaneko H ，Anzai T ，Horiuchi K ，Kohno T ，Nagai T ，Anzai A ，Takahashi T ，Sasaki A ，Shimoda M ，Maekawa Y ，Shimizu H ，Yoshikawa T ，Okada Y ，Yozu R ，Fukuda K ... -  《-》

Resveratrol prevents the development of abdominal aortic aneurysm through attenuation of inflammation, oxidative stress, and neovascularization.

We sought to examine the effect of resveratrol (3,4',5-trihydroxy-trans-stilbene), a plant-derived polyphenolic compound, on the development of abdominal aortic aneurysm (AAA). AAA was induced in mice by periaortic application of CaCl(2). NaCl (0.9%)-applied mice were used as a sham group. Mice were treated with intraperitoneal injection of PBS (Sham/CON, AAA/CON, n=30 for each) or resveratrol (100 mg/kg/day) (AAA/RSVT, n=30). Six weeks after the operation, aortic tissue was excised for further examinations. Aortic diameter was enlarged in AAA/CON compared with Sham/CON. Resveratrol treatment reduced the aneurysm size and inflammatory cell infiltration in the aortic wall compared with AAA/CON. Elastica Van Gieson staining showed destruction of the wavy morphology of the elastic lamellae in AAA/CON, while it was preserved in AAA/RSVT. The increased mRNA expression of monocyte chemotactic protein-1, tumor necrosis factor-α, intercellular adhesion molecule-1, CD68, vascular endothelial growth factor-A, p47, glutathione peroxidase (GPX)1 and GPX3 were attenuated by resveratrol treatment (all p<0.05). Administration of resveratrol decreased protein expression of phospho-p65 in AAA. The increased 8-hydroxy-2'-deoxyguanosine-positive cell count and 4-hydroxy-2-nonenal-positive cell count in AAA were also reduced by resveratrol treatment. Zymographic activity of matrix metalloproteinase (MMP)-9 and MMP-2 was lower in AAA/RSVT compared with AAA/CON (both p<0.05). Compared with AAA/CON, Mac-2(+) macrophages and CD31(+) vessels in the aortic wall were decreased in AAA/RSVT (both p<0.05). Treatment with resveratrol in mice prevented the development of CaCl(2)-induced AAA, in association with reduced inflammation, oxidative stress, neoangiogenesis, and extracellular matrix disruption. These findings suggest therapeutic potential of resveratrol for AAA.

Kaneko H ，Anzai T ，Morisawa M ，Kohno T ，Nagai T ，Anzai A ，Takahashi T ，Shimoda M ，Sasaki A ，Maekawa Y ，Yoshimura K ，Aoki H ，Tsubota K ，Yoshikawa T ，Okada Y ，Ogawa S ，Fukuda K ... -  《-》

Role of vascular endothelial growth factor-A in development of abdominal aortic aneurysm.

Kaneko H ，Anzai T ，Takahashi T ，Kohno T ，Shimoda M ，Sasaki A ，Shimizu H ，Nagai T ，Maekawa Y ，Yoshimura K ，Aoki H ，Yoshikawa T ，Okada Y ，Yozu R ，Ogawa S ，Fukuda K ... -  《-》

Expression and localization of tumour necrosis factor-alpha and its converting enzyme in human abdominal aortic aneurysm.

Satoh H ，Nakamura M ，Satoh M ，Nakajima T ，Izumoto H ，Maesawa C ，Kawazoe K ，Masuda T ，Hiramori K ... -  《CLINICAL SCIENCE》

Transglutaminase type 2 in human abdominal aortic aneurysm is a potential factor in the stabilization of extracellular matrix.

The aim of this study was to evaluate transglutaminase type 2 (TG2) expression in human abdominal aortic aneurysm (AAA) tissue and to elucidate a potential role of TG2 in AAA formation. TG2, which is a Ca(2+)-dependent cross-linking enzyme, has been proven important for stabilizing the extracellular matrix. However, there is no evidence of the effect of TG2 on AAA formation in a human model. Aortic wall tissues were obtained during surgery in AAA patients (n = 38) and in patients with aortoiliac occlusive disease (Control; n = 4) in the Asan Medical Center from March 2011 to February 2012. In each AAA patient, the aortic neck (Neck) and maximally dilated portion (Max) of the aneurysm were sampled for analysis. TG2 expression was evaluated using immunohistochemistry and Western blotting. In addition, ex vivo experiments of isolated AAA tissue culture with the TG2 inhibitor cystamine and recombinant human TG2 were performed. Among 38 AAA patients, 11 had ruptured (contained or free) AAAs. The mean maximal diameter of AAAs was 6.09 ± 1.46 cm. TG2 expressions of Max were significantly increased compared with those of Control (1.7-fold increase of Control; P = .00). Compared with Control, the intensities of tissue necrosis factor-α, matrix metalloproteinase (MMP)-2, MMP-9, and tissue inhibitors of metalloproteinase-2 were significantly upregulated in Max (1.7-fold, 1.5-fold, 1.3-fold, and 1.6-fold increases of Control; P = .00, P = .004, P = .046, and P = .007, respectively). Furthermore, double immunofluorescent staining showed that colocalization of TG2/transforming growth factor-β or TG2/fibronectin was prominent in Max compared with those of Neck or Control. In addition, MMP-2 intensity was upregulated in ruptured AAAs compared with unruptured AAAs, with marginal significance (P = .078). Ex vivo experiments showed that protein expressions of tissue necrosis factor-α, MMP-2, and MMP-9 in cultured AAA tissue were decreased by recombinant human TG2 but were increased by exogenous cystamine. The TG2 expression in the maximally dilated portion of AAAs was enhanced compared with that of nondilated aorta. It is suggested that TG2 has a potential effect in stabilization of extracellular matrix by inhibition of proinflammatory cytokines and MMPs or by interaction with fibronectin and transforming growth factor-β.

Shin S ，Cho YP ，Jun H ，Park H ，Hong HN ，Kwon TW ... -  《-》