Pharmacological inhibition of cathepsin S decreases atherosclerotic lesions in Apoe-/- mice.
Recent studies provided evidence for a significant role of cathepsin S during extracellular remodeling in atherosclerosis. In this study, we investigated the effect of a specific cathepsin S inhibitor on atherosclerotic plaque progression in the brachiocephalic artery. Male and female Apoe-/- mice on a cholate-containing high-fat diet containing or lacking a specific cathepsin S inhibitor were evaluated for the remodeling of atherosclerotic lesions. The in vivo efficacy of the cathepsin S inhibitor was demonstrated by the inhibition of invariant chain processing in spleen. After 8 weeks of diet, brachiocephalic arteries were analyzed for plaque size, collagen, macrophage, and smooth muscle cell content, for elastic lamina breaks, and the number of buried fibrous caps. The size of atherosclerotic plaques in inhibitor-treated mice was reduced by 36% in male and 68% in female mice, and they showed significantly smaller numbers in elastin lamina breaks (60% less in males; 75% less in females), plaque macrophages (47% less in males; 40% less in females), and buried fibrous caps (50% less in males; 86% less in females). In conclusion, the inhibition of cathepsin S showed a strong atheroprotective activity, demonstrating the potential benefits of a small molecule anti-cathepsin therapy.
Samokhin
Andriy O
AO
Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada.
Lythgo
Paul Ambrose
PA
Gauthier
Jacques Yves
JY
Percival
M David
MD
Brömme
Dieter
D
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000187:drug effects / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics; D016122:Brachiocephalic Trunk / Q000473:pathology; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004036:Diet, Atherogenic; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D012737:Sex Factors; D013154:Spleen / Q000187:drug effects / Q000473:pathology
D000944:Antigens, Differentiation, B-Lymphocyte; D001057:Apolipoproteins E; D000949:Histocompatibility Antigens Class II; C045084:invariant chain; D002403:Cathepsins; C028217:cathepsin S