title: TRAF3IP2 mediates atherosclerotic plaque development and vulnerability in ApoE(-/-) mice.
abstract: Atherosclerosis is a major cause of heart attack and stroke. Inflammation plays a critical role in the development of atherosclerosis. Since the cytoplasmic adaptor molecule TRAF3IP2 (TRAF3-Interacting Protein 2) plays a causal role in various autoimmune and inflammatory diseases, we hypothesized that TRAF3IP2 mediates atherosclerotic plaque development.
  
  
  
  TRAF3IP2/ApoE double knockout (DKO) mice were generated by crossing TRAF3IP2(-/-) and ApoE(-/-) mice. ApoE(-/-) mice served as controls. Both DKO and control mice were fed a high-fat diet for 12 weeks. Plasma lipids were measured by ELISA, atherosclerosis by en face analysis of aorta and plaque cross-section measurements at the aortic valve region, plaque necrotic core area, collagen and smooth muscle cell (SMC) content by histomorphometry, and aortic gene expression by RT-qPCR.
  
  
  
  The plasma lipoprotein profile was not altered by TRAF3IP2 gene deletion in ApoE(-/-) mice. While total aortic plaque area was decreased in DKO female, but not male mice, the plaque necrotic area was significantly decreased in DKO mice of both genders. Plaque collagen and SMC contents were increased significantly in both female and male DKO mice compared to respective controls. Aortic expression of proinflammatory cytokine (Tumor necrosis factor α, TNFα), chemokine (Chemokine (C-X-C motif) Ligand 1, CXCL1) and adhesion molecule (Vascular cell adhesion molecule 1, VCAM1; and Intercellular adhesion molecule 1, ICAM1) gene expression were decreased in both male and female DKO mice. In addition, the male DKO mice expressed markedly reduced levels of extracellular matrix (ECM)-related genes, including TIMP1 (Tissue inhibitor of metalloproteinase 1), RECK (Reversion-Inducing-Cysteine-Rich Protein with Kazal Motifs) and ADAM17 (A Disintegrin And Metalloproteinase 17).
  
  
  
  TRAF3IP2 plays a causal role in atherosclerotic plaque development and vulnerability, possibly by inducing the expression of multiple proinflammatory mediators. TRAF3IP2 could be a potential therapeutic target in atherosclerotic vascular diseases.
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, 70112, United States.
authors.forename: Siva Sankara Vara Prasad
authors.initials: SSVP
authors.lastname: Sakamuri
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, 70112, United States.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Higashi
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, 70112, United States.
authors.forename: Sergiy
authors.initials: S
authors.lastname: Sukhanov
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, 70112, United States.
authors.forename: Jalahalli M
authors.initials: JM
authors.lastname: Siddesha
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, 70112, United States.
authors.forename: Patrice
authors.initials: P
authors.lastname: Delafontaine
authors.affiliation: Laboratory of Immunoregulation, NIAID/NIH, Bethesda, MD, 20892, United States.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
authors.affiliation: Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, 70112, United States; HS Truman Memorial Veterans Hospital, 800 Hospital Drive, Columbia, MO, 75201, United States. Electronic address: chandrasekarb@health.missouri.edu.
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D050197:Atherosclerosis; D003094:Collagen / Q000378:metabolism; D003433:Crosses, Genetic; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D007249:Inflammation; D008074:Lipoproteins / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000074085:Mice, Knockout, ApoE; D009336:Necrosis; D058226:Plaque, Atherosclerotic / Q000235:genetics*; D012737:Sex Factors; D014280:Triglycerides / Q000097:blood
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008074:Lipoproteins; C515963:Traf3ip2 protein, mouse; D014280:Triglycerides; D003094:Collagen
keywords: Act1; Atherosclerosis; CIKS; Collagen; Plaque stability; TRAF3IP2