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Intimal hyperplasia (IH) is characterized by inflammatory cells infiltration and extensive smooth muscle cells proliferation that contributes to restenosis after percutaneous coronary intervention (PCI). Cathepsin L (CatL), a member of lysosome protease is highly expressed in mouse intimal hyperplasia lesions, but whether it contributes to the pathogenesis of IH remains unknown.
Carotid artery intimal hyperplasia was induced in WT and CatL KO (CatL-/-) mice by wire injured surgery, and IH lesions were analyzed after 28 days. Expression of CatL in the carotid lesions was analyzed by RT-PCR, Immunofluorescent staining and western blot. CatL's activity was measured by CathepsinL Activity Assay Kit (Fluorometric). Migration, proliferation and cytokine (MCP-1) production of bone marrow macrophages or smooth muscle cells derived from WT and CatL-/- mice were investigated. Vascular reactivity was studied in mice aortas.
We found that CatL expression and activity increased significantly in mouse IH lesions. The IH, intimal area and intimal/media ratio, in CatL-/- mice was significantly reduced than that in WT mice. CatL deficiency impaired macrophage infiltration 3 days after wire injury surgery, but did not affect smooth muscle cell or endothelial function directly. Proliferation and migration functions of smooth muscle cells derived from WT and CatL-/- aorta showed no significant difference. Aortic rings from WT and CatL-/- mice showed no significant difference in acetylcholine-induced endothelial relaxation responses. In vitro studies proved that production of inflammatory cytokine (MCP-1) and migration function of macrophages derived from CatL-/- mice, in response to LPS or HMGB1, were significantly impaired compared to WT macrophages.
These data provide direct evidence that CatL plays an important role in intimal hyperplasia formation and suggest that CatL is a new therapeutic target for vessel restenosis after PCI.