Abstract 5490: Cathepsin K Deficiency does not Affect Murine Aneurysm Formation However it Reduces Macrophage-Rich Neointima Formation in Apoe−/−Mice
Proteolytic arterial remodelling is a key process in various vasculopathies including restenosis and aortic aneurysm formation. One of the candidate effector proteases in both processes, may be cathepsin K (CatK), a potent lysosomal cysteine protease. We therefore hypothesized that a deficiency of this cystein protease could protect against these vascular pathologies. Firstly, we studied the effect of CatK deficiency on the intimal hyperplasia under normo-lipidemic (CatK−/− vs WT) and hyperlipidemic conditions (CatK−/−//ApoE−/− vs ApoE−/−) as induced by permanent ligation of the right carotid artery. Average neointima formation in hyperlipidemic CatK−/−//ApoE mice was significantly reduced compared to ApoE−/− mice (64%, p=0.02). Total vessel area was also significantly reduced in CatK−/−//ApoE−/− mice (46%, p=0.008 ). In contrast, catK deficiency did not affect SMC-rich neointima formation in normolipidemic mice as there was no difference in neointima size between CatK−/− mice and WT mice of C57BL/6 background. Secondly, we investigated the effect of CatK deficiency on angiotensin II-induced aneurysm formation in ApoE−/− mice. Contrary to our expectations, CatK deficiency did not protect against murine aneurysm formation. Strikingly, despite the similar aneurysm area, collagen content of aneurism lesions was 6-fold higher in CatK−/−//ApoE mice (p=0.04). Furthermore, we noticed a compensatory 71% and 90% increase, respectively, in the percentage of cathepsin S and cathepsin C positive cells in adventitia of CatK−/−//ApoE versus ApoE−/− mice (p=0.007 and 0.013, respectively). Taken these observations together, CatK deficiency appears to have divergent effects on restenosis and aneurysm formation only conferring protecting macrophage rich neointima formation in CatK−/−//ApoE−/− mice. Despite enhancing collagen content, CatK deficiency did not reduce aneurysm formation, which may be related to compensatory activation of other cathepsins in CatK deficiency. This also suggests that novel inhibitors selectively targeting CatK to intervene in pathogenic remodelling responses should be applied with caution.