Published online before print January 8, 2009

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(American Journal of Pathology. 2009;174:693-700.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080561

T-Cell Activation Leads to Reduced Collagen Maturation in Atherosclerotic Plaques of Apoe^–/– Mice

Olga Ovchinnikova^*, Anna-Karin L. Robertson^*, Dick Wågsäter^*, Eduardo J. Folco, Marjo Hyry, Johanna Myllyharju, Per Eriksson^*, Peter Libby and Göran K. Hansson^*

From the Center for Molecular Medicine and the Department of Medicine at Karolinska University Hospital,^* Karolinska Institute, Stockholm, Sweden; the Department of Internal Medicine No. 1, Pavlov State Medical University, St. Petersburg, Russia; the Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and the Oulu Centre for Cell-Matrix Research, Biocenter Oulu and the Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland

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 CD4dnTβRII mice with defective transforming growth factor-β 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 CD4dnTβRII 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^–/– – CD4dnTβRII mice. T-cell-driven inflammation provoked a selective and limited increase in the expression of proteinases that catabolize the extracellular matrix. Atheromata of Apoe^–/– – CD4dnTβRII 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.

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