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

Introduction: The link between cardiovascular disease (CVD) and patients suffering from 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 due to the hyperactivation of IkB kinases (IKKs) and mitogen activated protein kinases (MAPK). These mice were used to determine the potential role of these signalling 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 pro-atherogenic diet for 4 weeks, after which follow-up assessments were made. Paired and unpaired t-tests, ANOVA with post-hoc bonferroni correction were used for statistical significance P <0.05.
Results: Endothelium-dependent vasodilatation to acetylcholine was attenuated at four 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-1alpha 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 hyper-activation of IKKs and MAPKs might mediate chronic inflammation and CVD development.