title: An important role for A20-binding inhibitor of nuclear factor-kB-1 (ABIN1) in inflammation-mediated endothelial dysfunction: an in vivo study in ABIN1 (D485N) mice.
abstract: BACKGROUND
  The link between cardiovascular disease (CVD) and patients with chronic inflammation is not clearly understood. We examined a knock-in mouse expressing a poly-ubiquitin-binding-defective mutant of the protein ABIN1 (ABIN1(D485N)), which develops a systemic lupus erythematosus-like autoimmune disease because of the hyperactivation of IκB kinases (IκKs) and mitogen-activated protein kinases (MAPKs). These mice were used to determine the potential role of these signaling pathways in inflammation-mediated CVD development.
  
  
  METHODS
  Laser Doppler imaging in combination with the iontophoresis of vasoactive chemicals were used to assess endothelium-dependent vasodilatation in vivo in ABIN1 (D485N)) mutant defective (n=29) and wild-type (WT) control (n=26) mice. Measurements were made at baseline, and animals were subdivided to receive either chow or a proatherogenic diet for 4 weeks, after which, follow-up assessments were made. Paired and unpaired t tests, and ANOVA with post hoc Bonferroni correction were used for statistical significance at P<0.05.
  
  
  RESULTS
  Endothelium-dependent vasodilatation to acetylcholine was attenuated at 4 weeks in ABIN1(D485N)-chow-fed mice compared with age-matched WT-chow-fed mice (P<0.05). The magnitude of attenuation was similar to that observed in WT-cholesterol-fed animals (versus WT-chow, P<0.01). ABIN1(D485N)-cholesterol-fed mice had the poorest endothelium-dependent responses compared with other groups (P<0.001). ABIN1(D485N)-chow-fed mice had increased plasma interleukin-6 (IL-6) levels (versus WT-chow, P<0.001), and this was further elevated in ABIN1(D485N)-cholesterol-fed mice (versus ABIN1(D485N)-chow; P<0.05). IL-1α was significantly greater in all groups compared with WT-chow (P<0.01). ABIN1(D485N) mice showed significant cardiac hypertrophy (P<0.05).
  
  
  CONCLUSIONS
  The ABIN(D485N) mice display endothelial dysfunction and cardiac hypertrophy, which is possibly mediated through IL-6 and, to a lesser degree, IL-1α. These results suggest that the ABIN1-mediated hyperactivation of IKKs and MAPKs might mediate chronic inflammation and CVD development.
authors: Vascular and Inflammatory Diseases Research Unit, Medical Research Institute, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK. n.akbar@dundee.ac.uk.
authors: Naveed
authors: N
authors: Akbar
authors: MRC Protein Phosphorylation and Ubiquitylation Unit, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, UK. s.k.nanda@dundee.ac.uk.
authors: Sambit
authors: S
authors: Nanda
authors: Vascular and Inflammatory Diseases Research Unit, Medical Research Institute, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK. j.j.f.belch@dundee.ac.uk.
authors: Jill
authors: J
authors: Belch
authors: MRC Protein Phosphorylation and Ubiquitylation Unit, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, UK. p.cohen@dundee.ac.uk.
authors: Philip
authors: P
authors: Cohen
authors: Vascular and Inflammatory Diseases Research Unit, Medical Research Institute, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK. f.khan@dundee.ac.uk.
authors: Faisel
authors: F
authors: Khan
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006332:Cardiomegaly / Q000378:metabolism* / Q000503:physiopathology; D002784:Cholesterol / Q000008:administration & dosage; D003546:Cysteine Endopeptidases / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D055879:Gene Knock-In Techniques; D051550:I-kappa B Kinase / Q000097:blood; D007249:Inflammation / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D007478:Iontophoresis; D017078:Laser-Doppler Flowmetry; D008297:Male; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053582:Interleukin-1alpha; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; C503281:Tnip2 protein, mouse; D002784:Cholesterol; D051550:I-kappa B Kinase; D020929:Mitogen-Activated Protein Kinase Kinases; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse; D000109:Acetylcholine
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