| First Author | Kitamoto S | Year | 2007 |
| Journal | Circulation | Volume | 115 |
| Issue | 15 | Pages | 2065-75 |
| PubMed ID | 17404153 | Mgi Jnum | J:135371 |
| Mgi Id | MGI:3793526 | Doi | 10.1161/CIRCULATIONAHA.107.688523 |
| Citation | Kitamoto S, et al. (2007) Cathepsin L deficiency reduces diet-induced atherosclerosis in low-density lipoprotein receptor-knockout mice. Circulation 115(15):2065-75 |
| abstractText | BACKGROUND: Remodeling of the arterial extracellular matrix participates importantly in atherogenesis and plaque complication. Increased expression of the elastinolytic and collagenolytic enzyme cathepsin L (Cat L) in human atherosclerotic lesions suggests its participation in these processes, a hypothesis tested here in mice. METHODS AND RESULTS: We generated Cat L and low-density lipoprotein receptor (LDLr) double-deficient (LDLr-/- Cat L-/-) mice by crossbreeding Cat L-null (Cat L-/-) and LDLr-deficient (LDLr-/-) mice. After 12 and 26 weeks of a Western diet, LDLr-/- Cat L-/- mice had significantly smaller atherosclerotic lesions and lipid cores compared with littermate control LDLr-/- Cat L+/- and LDLr-/- Cat L+/+ mice. In addition, lesions from the compound mutant mice showed significantly reduced levels of collagen, medial elastin degradation, CD4+ T cells, macrophages, and smooth muscle cells. Mechanistic studies showed that Cat L contributes to the degradation of extracellular matrix elastin and collagen by aortic smooth muscle cells. Smooth muscle cells from LDLr-/- Cat L-/- mice or those treated with a Cat L-selective inhibitor demonstrated significantly less degradation of elastin and collagen and delayed transmigration through elastin in vitro. Cat L deficiency also significantly impaired monocyte and T-lymphocyte transmigration through a collagen matrix in vitro, suggesting that blood-borne leukocyte penetration through the arterial basement membrane requires Cat L. Cysteine protease active site labeling demonstrated that Cat L deficiency did not affect the activity of other atherosclerosis-associated cathepsins in aortic smooth muscle cells and monocytes. CONCLUSIONS: Cat L directly participates in atherosclerosis by degrading elastin and collagen and regulates blood-borne leukocyte transmigration and lesion progression. |
