INTRODUCTION: 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.
Arthritis Res Ther
Acetylcholine, Adaptor Proteins, Signal Transducing, Animals, Autoimmune Diseases, Cardiomegaly, Cholesterol, Cysteine Endopeptidases, Endothelium, Vascular, Gene Knock-In Techniques, I-kappa B Kinase, Inflammation, Interleukin-1alpha, Interleukin-6, Intracellular Signaling Peptides and Proteins, Iontophoresis, Laser-Doppler Flowmetry, Male, Mice, Mitogen-Activated Protein Kinase Kinases, Signal Transduction, Tumor Necrosis Factor alpha-Induced Protein 3