Transglutaminase 2 deficiency decreases plaque fibrosis and increases plaque inflammation in apolipoprotein-E-deficient mice.
OBJECTIVE
Transglutaminase 2 (TG2) is important for the deposition and stability of the extracellular matrix via effects on cross-linking of matrix proteins and transforming growth factor beta (TGFbeta) activity. The purpose of this study was to investigate the effect of TG2 deficiency on the composi- tion of atherosclerotic plaques.


METHODS
Apolipoprotein E (ApoE)(-/-) mice were crossbred with TG2(-/-) mice to obtain ApoE(-/-)TG2(-/-) mice. ApoE(-/-) and ApoE(-/-)TG2(-/-) mice were fed a Western-type diet for 16 or 30 weeks to determine the effect of TG2 deficiency on early and advanced atherosclerosis, respectively.


RESULTS
Atherosclerotic plaques of ApoE(-/-)TG2(-/-) mice showed decreased cross-linking of matrix proteins, as well as decreased nuclear staining for phospho-Smad2/-Smad3, indicative of decreased TGFbeta activity. Compared to ApoE(-/-) mice, plaque area was decreased by 45 and 48% in ApoE(-/-)TG2(-/-) mice after 16 and 30 weeks, respectively. Sirius red staining showed a significant decrease in collagen content in early and advanced atherosclerotic plaques of ApoE(-/-)TG2(-/-) mice. Furthermore, there was a significant increase in macrophages in advanced atherosclerotic plaques of ApoE(-/-)TG2(-/-) mice.


CONCLUSIONS
TG2 deficiency resulted in a decreased collagen content and increased inflammation, which are features of a more unstable plaque.
Van Herck
Jozef L
JL
Division of Cardiology, Antwerp University Hospital, Edegem, Belgium. jozef.vanherck@ua.ac.be
Schrijvers
Dorien M
DM
De Meyer
Guido R Y
GR
Martinet
Wim
W
Van Hove
Cor E
CE
Bult
Hidde
H
Vrints
Christiaan J
CJ
Herman
Arnold G
AG
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D019204:GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012421:Rupture; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D011503:Transglutaminases / Q000172:deficiency* / Q000235:genetics
D001057:Apolipoproteins E; D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D003094:Collagen; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins