title: Apoptosis signal-regulating kinase 1 deficiency accelerates hyperlipidemia-induced atheromatous plaques via suppression of macrophage apoptosis.
abstract: OBJECTIVE
  The pathogenic role of macrophage apoptosis in atherosclerosis is still debatable, but it is considered to be a suppressor of plaque progression in early stages but a promoter of plaque necrosis in advanced stages. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a pivotal role in stress-induced apoptosis. In the current study, we investigated the functions of ASK1 in hyperlipidemia-induced atherosclerosis.
  
  
  RESULTS
  We generated ASK1 and apolipoprotein E (apoE) double-knockout mice (ASK1(-/-)/apoE(-/-)) and analyzed atherosclerosis in ASK1(-/-)/apoE(-/-) mice fed a high-cholesterol diet for 12 weeks. ASK1(-/-)/apoE(-/-) mice had accelerated hyperlipidemia-induced atherosclerosis, which was characterized by less apoptosis of macrophages and fewer necrotic areas, and more macrophages and elastolysis compared with apoE(-/-) mice. Bone marrow transplantation from ASK1(-/-) or wild-type to apoE(-/-) mice confirmed the above observation that the recipient mice of ASK1(-/-) donors had more pronounced hyperlipidemia-induced atherosclerosis than recipient mice of wild-type donors.
  
  
  CONCLUSIONS
  These findings suggest that ASK1 suppresses hyperlipidemia-induced atherosclerosis via increased macrophage apoptosis and that ASK1 may cause pronounced plaque vulnerability via necrotic core development.
authors.affiliation: Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. yasu3219@med.uoeh-u.ac.jp
authors.forename: Sohsuke
authors.initials: S
authors.lastname: Yamada
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Akihide
authors.initials: A
authors.lastname: Tanimoto
authors.forename: Ke-Yong
authors.initials: KY
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.forename: Takashi
authors.initials: T
authors.lastname: Tasaki
authors.forename: Atsunori
authors.initials: A
authors.lastname: Nabesima
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Murata
authors.forename: Shohei
authors.initials: S
authors.lastname: Shimajiri
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Kohno
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sasaguri
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis; D001835:Body Weight; D016026:Bone Marrow Transplantation; D002791:Cholesterol, Dietary; D004195:Disease Models, Animal; D004547:Elastic Tissue / Q000378:metabolism; D005487:Foam Cells / Q000201:enzymology* / Q000473:pathology; D006949:Hyperlipidemias / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D007150:Immunohistochemistry; D008074:Lipoproteins / Q000097:blood; D048848:MAP Kinase Kinase Kinase 5 / Q000172:deficiency* / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D058226:Plaque, Atherosclerotic / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D008074:Lipoproteins; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse