O229	Atherosclerotic lesions with exaggerated inflammation show impaired collagen maturation.
O.Ovtchinnikova, A-K.Robertson, G.K.Hansson
Karolinska Institute, Stockholm, SE.

Background: Atherosclerotic plaque stability is determined by the integrity of the fibrous cap, which consists mainly of collagen fibers. Unstable plaques are rich in activated immune cells, which may initiate plaque activation by secreting cytokines and proteases that destabilize the plaque. It was proposed that IFN-γ- producing T cells play an important role in plaque destabilization by reducing collagen synthesis and inhibiting the proliferative response of smooth muscle cells. The aim of this study was to determine the relationship between T cell-mediated inflammation and collagen composition in the atherosclerotic plaque. Methods and results: In this study we used ApoE-deficient mice with defective TGF-β receptors in T-lymphocytes (E0 x CD4dnT-βRII). These mice exhibit elevated systemic inflammatory activity with dramatically increased IFN-γ production and develop very large and inflamed atherosclerotic lesions. Lesion size-matched ApoE-deficient mice (E0) were used as controls. Collagen fibers in lesions were stained with Picrosirius Red and visualized in polarized light. The relative amount of thick mature collagen fibers was significantly reduced in E0 x CD4dnT-βRII mice. In contrast, this group showed a tendency towards a higher content of thin immature fibers, implying a more vulnerable plaque phenotype. No significant difference in total collagen content was observed between two groups. Quantitative RT-PCR analysis showed a significant decrease in mRNA expression of prolyl 4-hydroxylase, a key enzyme in the process of collagen maturation. Surprisingly, no significant changes of procollagen I or procollagen III mRNA abundance were found in total aorta from E0 x CD4dnT-βRII mice compared with E0 mice These data imply that T cell-mediated inflammation inhibits the processing of collagen fibers but has minor effects on collagen gene expression. Conclusion: Our results suggest that weakening of atherosclerotic plaque in conditions of exaggerated inflammatory response is due to impaired collagen organization. This is likely regulated by posttranslational mechanisms affecting collagen fiber maturation.

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