T-cell activation leads to reduced collagen maturation in atherosclerotic plaques of Apoe(-/-) mice.
Rupture of the collagenous, fibrous cap of an atherosclerotic plaque commonly causes thrombosis. Activated immune cells can secrete mediators that jeopardize the integrity of the fibrous cap. This study aimed to determine the relationship between T-cell-mediated inflammation and collagen turnover in a mouse model of experimental atherosclerosis. Both Apoe(-/-) x CD4dnTbetaRII mice with defective transforming growth factor-beta receptors in T cells (and hence released from tonic suppression of T-cell activation) and lesion size-matched Apoe(-/-) mice were used. Picrosirius red staining showed a lower content of thick mature collagen fibers in lesions of Apoe(-/-) x CD4dnTbetaRII mice, although both groups had similar levels of procollagen type I or III mRNA and total collagen content in lesions. Analysis of both gene expression and protein content showed a significant decrease of lysyl oxidase, the extracellular enzyme needed for collagen cross-linking, in aortas of Apoe(-/-)--CD4dnTbetaRII mice. T-cell-driven inflammation provoked a selective and limited increase in the expression of proteinases that catabolize the extracellular matrix. Atheromata of Apoe(-/-)--CD4dnTbetaRII mice had increased levels of matrix metalloproteinase-13 and cathepsin S mRNAs and of the active form of cathepsin S protein but no increase was detected in collagen fragmentation. Our results suggest that exaggerated T-cell-driven inflammation limits collagen maturation in the atherosclerotic plaque while having little effect on collagen degradation.
Ovchinnikova
Olga
O
Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
Robertson
Anna-Karin L
AK
Wågsäter
Dick
D
Folco
Eduardo J
EJ
Hyry
Marjo
M
Myllyharju
Johanna
J
Eriksson
Per
P
Libby
Peter
P
Hansson
Göran K
GK
D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology; D015153:Blotting, Western; D003094:Collagen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008249:Protein-Lysine 6-Oxidase / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*
D001057:Apolipoproteins E; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase