title: Cathepsin S deficiency results in abnormal accumulation of autophagosomes in macrophages and enhances Ang II-induced cardiac inflammation.
abstract: BACKGROUND
  Cathepsin S (Cat S) is overexpressed in human atherosclerotic and aneurysmal tissues and may contributes to degradation of extracellular matrix, especially elastin, in inflammatory diseases. We aimed to define the role of Cat S in cardiac inflammation and fibrosis induced by angiotensin II (Ang II) in mice.
  
  
  RESULTS
  Cat S-knockout (Cat S(-/-)) and littermate wild-type (WT) C57BL/6J mice were infused continuously with Ang II (750 ng/kg/min) or saline for 7 days. Cat S(-/-) mice showed severe cardiac fibrosis, including elevated expression of collagen I and α-smooth muscle actin (α-SMA), as compared with WT mice. Moreover, macrophage infiltration and expression of inflammatory cytokines (tumor necrosis factor α, transforming growth factor β and interleukin 1β) were significantly greater in Cat S(-/-) than WT hearts. These Ang II-induced effects in Cat S(-/-) mouse hearts was associated with abnormal accumulation of autophagosomes and reduced clearance of damaged mitochondria, which led to increased levels of reactive oxygen species (ROS) and activation of nuclear factor-kappa B (NF-κB) in macrophages.
  
  
  CONCLUSIONS
  Cat S in lysosomes is essential for mitophagy processing in macrophages, deficiency in Cat S can increase damaged mitochondria and elevate ROS levels and NF-κB activity in hypertensive mice, so it regulates cardiac inflammation and fibrosis.
authors.affiliation: Beijing An Zhen Hospital Affiliated to Capital Medical University, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Pan
authors.forename: Yulin
authors.initials: Y
authors.lastname: Li
authors.forename: Lixin
authors.initials: L
authors.lastname: Jia
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Qin
authors.forename: Guanming
authors.initials: G
authors.lastname: Qi
authors.forename: Jizhong
authors.initials: J
authors.lastname: Cheng
authors.forename: Yongfen
authors.initials: Y
authors.lastname: Qi
authors.forename: Huihua
authors.initials: H
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Du
mesh_terms: D000783:Aneurysm / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology; D015153:Blotting, Western; D002403:Cathepsins / Q000172:deficiency*; D017931:DNA Primers / Q000235:genetics; D006652:Histological Techniques; D007150:Immunohistochemistry; D002537:Intracranial Arteriosclerosis / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D002403:Cathepsins; C028217:cathepsin S