Cathepsin K Deficiency Reduces Elastase Perfusion–Induced Abdominal Aortic Aneurysms in Mice

Abstract

Objectives Cathepsin K (CatK) is one of the most potent mammalian elastases. We have previously shown increased expression of CatK in human abdominal aortic aneurysm (AAA) lesions. Whether this protease participates directly in AAA formation, however, remains unknown. Methods and Results Mouse experimental AAA was induced with aortic perfusion of a porcine pancreatic elastase. Using this experimental model, we demonstrated that absence of CatK prevented AAA formation in mice 14 days post-perfusion. CatK deficiency significantly reduced lesion CD4+ T-cellcontent, total lesion and medial cell proliferation and apoptosis, medial smooth-muscle cell (SMC) loss, elastinolytic CatL and CatS expression, and elastin fragmentation, but did not affect AAA lesion Mac-3+ macrophage accumulation or CD31+ microvessel numbers. In vitro studies revealed that CatK contributed importantly to CD4+ T-cell proliferation, SMC apoptosis, and other cysteinyl cathepsin and matrix metalloproteinase expression and activities in SMC and endothelial cells, but played negligible roles in microvessel growth and monocyte migration. AAA lesions from CatK-deficient mice showed reduced elastinolytic cathepsin activities compared with those from wild-type control mice. Conclusion This study demonstrates that CatK plays an essential role in AAA formation by promoting T-cell proliferation, vascular SMC apoptosis, and elastin degradation, and by affecting vascular cell protease expression and activities.

Cathepsin K-mediated notch1 activation contributes to neovascularization in response to hypoxia

“…Previous studies using CatK knockout animals provide evidence that CatK specifically mediates biological effects in cellular events 21,30 . In line with these findings, our results showed that blood flow recovery and capillary formation following hindlimb ischaemia were substantially impaired in CatK À / À mice.…”

“…Notch1 signalling regulates EC activity in postnatal angiogenesis 17 . CatK is expressed on proliferating vascular and inflammatory cells during vascular remodelling 5 , and genetic deletion of CatK suppresses cell proliferation and migration infiltration in vivo 21 . Therefore, we assessed whether the blockade of CatK by two small interfering CatK-silencing RNAs (siCatK25 and 26) affects Notch1 activation and EC function.…”

Cysteine Protease Cathepsins in Atherosclerosis-Based Vascular Disease and Its Complications

“…69 These mice also showed enhanced inflammatory cell accumulation, more severe elastin break, and fewer SMCs in the tunica media than the control mice (Table). Recently, Sun et al 70,71 have demonstrated that cathepsin L or K reduces elastase perfusion-induced AAAs in ApoE Ϫ/Ϫ mice. These findings suggest that imbalanced proteolytic activities in the vascular wall, resulting in excessive matrix destruction and progressive weakening of the arterial wall, are among the hallmarks of AAA pathology.…”

Activation of the vitamin D receptor selectively interferes with calcineurin-mediated inflammation: a clinical evaluation in the abdominal aortic aneurysm

“…Table 2 Relative mRNA expression of selected inflammatory mediators, proteases, cytokines, and cell activation markers (log transcript level relative to GAPDH (GAPDH = 0)) Vitamin D receptor activation and vascular inflammation AJ Nieuwland et al A critical point is whether the observed effects of VDR activation are beneficial in the context of AAA disease or vascular disease in general (atherosclerosis). Although cathepsin K 29 and L 30 have both been implicated in the process of aneurysm formation, 31 an apparent dominant role in AAA progression is challenged by the observation that reductions in cathepsin K and L expression during, respectively, statin 28 and ACE inhibitor therapy 27 are not followed by an effect on aneurysms growth. It is unclear whether and if the effects of VDR activation on T-helper cell content will influence AAA disease.…”