OBJECTIVE: A dysbalance of proteases and their inhibitors is instrumental in remodeling of atherosclerotic plaques. One of the proteases implicated in matrix degradation is cathepsin-S (CatS). To address its role in advanced lesion composition, we generated chimeric LDLr(-/-) mice deficient in leukocyte CatS by transplantation with CatS(-/-)xLDLr(-/-) or with LDLr(-/-) bone marrow and administered a high-fat diet. METHODS AND RESULTS: No difference in aortic root lesion size could be detected between CatS(+/+) and CatS(-/-) chimeras. However, leukocyte CatS deficiency markedly changed plaque morphology and led to a dramatic reduction in necrotic core area by 77% and an abundance of large foam cells. Plaques of CatS(-/-) chimeras contained 17% more macrophages, 62% less SMCs, and 33% less intimal collagen. The latter two could be explained by a reduced number of elastic lamina fractures. Moreover, macrophage apoptosis was reduced by 60% with CatS deficiency. In vitro, CatS was found to be involved in cholesterol metabolism and in macrophage apoptosis in a collagen and fibronectin matrix. CONCLUSIONS: Leukocyte CatS deficiency results in considerably altered plaque morphology, with smaller necrotic cores, reduced apoptosis, and decreased SMC content and collagen deposition and may thus be critical in plaque stability.
OBJECTIVE: A dysbalance of proteases and their inhibitors is instrumental in remodeling of atherosclerotic plaques. One of the proteases implicated in matrix degradation is cathepsin-S (CatS). To address its role in advanced lesion composition, we generated chimeric LDLr(-/-) mice deficient in leukocyte CatS by transplantation with CatS(-/-)xLDLr(-/-) or with LDLr(-/-) bone marrow and administered a high-fat diet. METHODS AND RESULTS: No difference in aortic root lesion size could be detected between CatS(+/+) and CatS(-/-) chimeras. However, leukocyte CatS deficiency markedly changed plaque morphology and led to a dramatic reduction in necrotic core area by 77% and an abundance of large foam cells. Plaques of CatS(-/-) chimeras contained 17% more macrophages, 62% less SMCs, and 33% less intimal collagen. The latter two could be explained by a reduced number of elastic lamina fractures. Moreover, macrophage apoptosis was reduced by 60% with CatS deficiency. In vitro, CatS was found to be involved in cholesterol metabolism and in macrophage apoptosis in a collagen and fibronectin matrix. CONCLUSIONS:Leukocyte CatS deficiency results in considerably altered plaque morphology, with smaller necrotic cores, reduced apoptosis, and decreased SMC content and collagen deposition and may thus be critical in plaque stability.
Authors: Veronica Herías; Erik A L Biessen; Cora Beckers; Dianne Delsing; Mengyang Liao; Mat J Daemen; Christine C T N Pham; Sylvia Heeneman Journal: Arterioscler Thromb Vasc Biol Date: 2014-11-13 Impact factor: 8.311
Authors: Manu O Platt; Denise Evans; Philip M Keegan; Lynne McNamara; Ivana K Parker; LaDeidra M Roberts; Alexander W Caulk; Rudolph L Gleason; Daniel Seifu; Wondwossen Amogne; Clement Penny Journal: Mol Biotechnol Date: 2016-01 Impact factor: 2.695
Authors: Santhosh Kumar Vr; Murthy N Darisipudi; Stefanie Steiger; Satish Kumar Devarapu; Maia Tato; Onkar P Kukarni; Shrikant R Mulay; Dana Thomasova; Bastian Popper; Jana Demleitner; Gabriele Zuchtriegel; Christoph Reichel; Clemens D Cohen; Maja T Lindenmeyer; Helen Liapis; Solange Moll; Emma Reid; Alan W Stitt; Brigitte Schott; Sabine Gruner; Wolfgang Haap; Martin Ebeling; Guido Hartmann; Hans-Joachim Anders Journal: J Am Soc Nephrol Date: 2015-11-13 Impact factor: 10.121