Abstract 8377: Cathepsin K Deficiency Suppresses the Development of Experimental Intimal Hyperplasia in Response to Injury

Abstract

Background. Cathepsin K (Cat K), a potent elastinolytic and collagenolytic cysteine protease, is considered likely to participate in the development and destabilization of atherosclerotic plaques. In order to define the role of Cat K in arterial remodeling, we evaluated the influence of the targeted deletion of the Cat K gene (Cat K−/−) on vascular remodeling after flow cessation in murine carotid arteries. Methods and Results. Male Cat K+/+ and Cat K−/− mice receiving normal chow underwent ligation or ligation/polyethylene cuff-placement injuries to the left common carotid artery just proximal to its bifurcation, and were then processed for morphological and biochemical studies at specific time points. There were no changes in the expression of Cat K mRNA or protein in the basal or injured arteries. Histological analysis revealed that there was significantly less intimal hyperplasia in Cat K−/− mice than in control mice at 28 days after surgery. At Day 4 after surgery, the amounts of mRNA for MMP-9, MMP-14, toll-like receptor-4 (TLR-4), chemokine ligand 12 (CCL12) and the contents of macrophages were significantly lower in both the single- and double-injured arteries of Cat K−/− mice than in corresponding model of Cat K+/+ mice. At Day 7, gelatin zymography showed that MMP-9 activity increased in the injured arteries of both types in Cat K+/+ mice. An ex vivo migration assay showed that Cat K deficiency impaired smooth muscle cell migration from aortic explants. Although there were no differences in SMC adhesion or apoptosis in mice of either genotype, Cat K deficiency impaired chemoattractant-directed SMC and macrophage invasions. Synthetic cathepsin inhibitor E64d inhibited ligation-induced neointima formation in Cat K+/+ mice but a deficiency of endogenous inhibitor cystatin C deteriorated the neointima in apoliporotein E deficiency mice. ELISA demonstrated that Cat K−/− mice had lower levels of plasma stromal-derived factor-1 and interleukin-1β. Conclusions. This study demonstrates an essential role of Cat K in atherosclerotic lesion formation in response to injury, possibly via the reduction of inflammation and SMC formation, suggesting a novel therapeutic strategy for the control of atherosclerosis by regulating Cat K activity.