title: Receptor-interacting protein kinase 3 contributes to abdominal aortic aneurysms via smooth muscle cell necrosis and inflammation.
abstract: BACKGROUND
  Depletion of medial smooth muscle cell (SMC) is a major pathological characteristic of abdominal aortic aneurysm (AAA), although the mechanism by which these cells are eliminated remains incompletely understood. We reasoned that necroptosis, a recently described form of necrosis mediated by receptor-interacting protein kinase 3 (RIP3), may contribute to AAA pathology through the induction of SMC death and the significant production of inflammatory cytokines.
  
  
  OBJECTIVE
  To test the hypothesis that RIP3-mediated necroptosis is actively involved in aneurysm pathogenesis.
  
  
  RESULTS
  RIP3 and RIP1 levels were found to be elevated in human AAAs, most noticeably in SMCs. Elevations of RIP3 and SMC necrosis were also observed in the elastase-induced mouse model of AAAs. Deletion of one or both copies of Rip3 prevented AAA formation. By transplanting Rip3(+/-) aortae to Rip3(+/+) mice, we demonstrated that reduced Rip3 expression in arterial wall was the primary cause of aneurysm resistance. In vitro, adenoviral overexpression of RIP3 was sufficient to trigger SMC necroptosis. Protein kinase C-delta contributed to tumor necrosis factor-α-induced SMC necroptosis by regulating Rip3 expression. Furthermore, Rip3 deficiency impaired tumor necrosis factor-α-induced inflammatory gene expression in aortic SMCs, which was at least in part because of attenuation of p65 Ser536 phosphorylation. In vivo, the lack of RIP3 diminished activation of p65 in SMCs, implicating a necrosis independent function of RIP3 in aneurysms.
  
  
  CONCLUSIONS
  Enhanced RIP3 signaling in aneurysmal tissues contributes to AAA progression by causing SMC necroptosis, as well as stimulating vascular inflammation, and therefore may serve as a novel therapeutic target for AAA treatment.
authors.affiliation: From the Department of Surgery (Q.W., Z.L., J.R., S.M., C.A., B.L.), Department of Pathology and Laboratory Medicine, School of Medicine and Public Health (Q.W., B.L.), and Cellular and Molecular Pathology Training Program, University of Wisconsin-Madison (Q.W., B.L.); and Department of Vascular Surgery, the Second Affiliated Hospital School of Medicine, Zhejiang University, China (Z.L.).
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Wang
authors.affiliation: From the Department of Surgery (Q.W., Z.L., J.R., S.M., C.A., B.L.), Department of Pathology and Laboratory Medicine, School of Medicine and Public Health (Q.W., B.L.), and Cellular and Molecular Pathology Training Program, University of Wisconsin-Madison (Q.W., B.L.); and Department of Vascular Surgery, the Second Affiliated Hospital School of Medicine, Zhejiang University, China (Z.L.).
authors.forename: Zhenjie
authors.initials: Z
authors.lastname: Liu
authors.affiliation: From the Department of Surgery (Q.W., Z.L., J.R., S.M., C.A., B.L.), Department of Pathology and Laboratory Medicine, School of Medicine and Public Health (Q.W., B.L.), and Cellular and Molecular Pathology Training Program, University of Wisconsin-Madison (Q.W., B.L.); and Department of Vascular Surgery, the Second Affiliated Hospital School of Medicine, Zhejiang University, China (Z.L.).
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.affiliation: From the Department of Surgery (Q.W., Z.L., J.R., S.M., C.A., B.L.), Department of Pathology and Laboratory Medicine, School of Medicine and Public Health (Q.W., B.L.), and Cellular and Molecular Pathology Training Program, University of Wisconsin-Madison (Q.W., B.L.); and Department of Vascular Surgery, the Second Affiliated Hospital School of Medicine, Zhejiang University, China (Z.L.).
authors.forename: Stephanie
authors.initials: S
authors.lastname: Morgan
authors.affiliation: From the Department of Surgery (Q.W., Z.L., J.R., S.M., C.A., B.L.), Department of Pathology and Laboratory Medicine, School of Medicine and Public Health (Q.W., B.L.), and Cellular and Molecular Pathology Training Program, University of Wisconsin-Madison (Q.W., B.L.); and Department of Vascular Surgery, the Second Affiliated Hospital School of Medicine, Zhejiang University, China (Z.L.).
authors.forename: Carmel
authors.initials: C
authors.lastname: Assa
authors.affiliation: From the Department of Surgery (Q.W., Z.L., J.R., S.M., C.A., B.L.), Department of Pathology and Laboratory Medicine, School of Medicine and Public Health (Q.W., B.L.), and Cellular and Molecular Pathology Training Program, University of Wisconsin-Madison (Q.W., B.L.); and Department of Vascular Surgery, the Second Affiliated Hospital School of Medicine, Zhejiang University, China (Z.L.). liub@surgery.wisc.edu.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000201:enzymology / Q000473:pathology / Q000637:transplantation; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology / Q000637:transplantation; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology / Q000637:transplantation; D009336:Necrosis; D010196:Pancreatic Elastase; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C497259:Prkcd protein, mouse; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D051745:Protein Kinase C-delta; D010196:Pancreatic Elastase
keywords: Rip3 protein, mouse; aortic aneurysm, abdominal; apoptosis; myocytes, smooth muscle; necrosis; nuclear factor kappa B; protein kinase C-delta