Activation of transglutaminase type 2 for aortic wall protection in a rat abdominal aortic aneurysm formation.
OBJECTIVE
The altered structure and composition of the vascular extracellular matrix (ECM) influences the formation of abdominal aortic aneurysms (AAA). Transglutaminase type 2 (TG2), which is a Ca(2+)-dependent cross-linking enzyme, has been proven the importance for ECM homeostasis, but there is no evidence of TG2 in AAA formation. The hypothesis was investigated that TG2 contributes to protect aortic walls during remodeling of the AAAs.


METHODS
In a rat abdominal aortic aneurysm model using a combination of intraluminal elastase infusion and extraluminal calcium chloride, TG2 expression and activity were evaluated at 1 and 8 weeks after the AAA preparation (n = 6 at each endpoint), compared with those of the non-prepared aorta (n = 6). Additionally, ex vivo experiments of isolated AAA tissue culture with recombinant human TG2, TG2 inhibitor cystamine, or tissue necrosis factor (TNF)-α were performed.


RESULTS
TG2 mRNA expression in the AAAs was significantly upregulated at both 1 and 8 weeks (22.4-fold and 5.4-fold increases of the non-prepared aorta, P = .0022 and P = .0048, respectively). TG2 protein expression and activity were also enhanced by fluorescent staining of the AAAs. Similar mRNA upregulation of TNF-α, interleukin-1β, matrix metalloproteinases (MMP)-2, MMP-9, and tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2 was observed in the AAAs, and TG2 and TNF-α were colocalized in the aortic walls at 1 week. Ex vivo experiments showed that mRNA expressions of TNF-α, MMP-2, and MMP-9 in the cultured AAA tissue were decreased by exogenous TG2, whereas were increased by cystamine. TNF-α exposure to the AAA tissues was significantly upregulated TG2 mRNA expression (P = .0333).


CONCLUSIONS
TG2 expression and activity in AAA formation were enhanced, possibly due to compensatory reaction. TG2 has a potential role of ECM protector in aortic walls during remodeling of the AAAs.
Munezane
Takashi
T
Department of Surgery, Division of Cardiovascular Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
Hasegawa
Tomomi
T
Suritala
Tanaka
Akiko
A
Okada
Kenji
K
Okita
Yutaka
Y
D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000201:enzymology*; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D002122:Calcium Chloride; D003538:Cystamine / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D010196:Pancreatic Elastase; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D046509:Tissue Culture Techniques; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D012333:RNA, Messenger; D011994:Recombinant Proteins; C000717609:Tgm2 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D019716:Tissue Inhibitor of Metalloproteinase-2; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D010196:Pancreatic Elastase; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; D019204:GTP-Binding Proteins; D002122:Calcium Chloride; D003538:Cystamine