title: Transglutaminase type 2 in human abdominal aortic aneurysm is a potential factor in the stabilization of extracellular matrix.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Vascular Surgery, Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea.
authors.forename: Sung
authors.initials: S
authors.lastname: Shin
authors.forename: Yong-Pil
authors.initials: YP
authors.lastname: Cho
authors.forename: Heungman
authors.initials: H
authors.lastname: Jun
authors.forename: Hojong
authors.initials: H
authors.lastname: Park
authors.forename: Hea Nam
authors.initials: HN
authors.lastname: Hong
authors.forename: Tae-Won
authors.initials: TW
authors.lastname: Kwon
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001012:Aorta, Abdominal / Q000000981:diagnostic imaging / Q000187:drug effects / Q000201:enzymology*; D017544:Aortic Aneurysm, Abdominal / Q000000981:diagnostic imaging / Q000201:enzymology*; D001019:Aortic Rupture / Q000000981:diagnostic imaging / Q000201:enzymology*; D001027:Aortography / Q000379:methods; D015153:Blotting, Western; D016022:Case-Control Studies; D003538:Cystamine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D019204:GTP-Binding Proteins; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011994:Recombinant Proteins / Q000378:metabolism; D056910:Republic of Korea; D046509:Tissue Culture Techniques; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D005353:Fibronectins; D018836:Inflammation Mediators; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; C560823:TIMP2 protein, human; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D019716:Tissue Inhibitor of Metalloproteinase-2; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D019204:GTP-Binding Proteins; D003538:Cystamine