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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.

Akbar N, Nanda S, Belch J, Cohen P, Khan F - Arthritis Res. Ther. (2015)

Bottom Line: The magnitude of attenuation was similar to that observed in WT-cholesterol-fed animals (versus WT-chow, P<0.01).IL-1α was significantly greater in all groups compared with WT-chow (P<0.01).These results suggest that the ABIN1-mediated hyperactivation of IKKs and MAPKs might mediate chronic inflammation and CVD development.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Follow-up vascular function. Microvascular responses at 4 weeks to (A) endothelium-dependent acetylcholine in WT-chow (n = 11), WT-cholesterol (n = 11), ABIN1[D485N]-chow (n = 10), and ABIN1[D485N]-cholesterol (n = 10)-fed mice; and (B) endothelium-independent sodium nitroprusside in the same mice (% change ± SEM). One-way ANOVA with post hoc Bonferroni correction. *P <0.05; **P <0.01; ***P <0.001.
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Fig5: Follow-up vascular function. Microvascular responses at 4 weeks to (A) endothelium-dependent acetylcholine in WT-chow (n = 11), WT-cholesterol (n = 11), ABIN1[D485N]-chow (n = 10), and ABIN1[D485N]-cholesterol (n = 10)-fed mice; and (B) endothelium-independent sodium nitroprusside in the same mice (% change ± SEM). One-way ANOVA with post hoc Bonferroni correction. *P <0.05; **P <0.01; ***P <0.001.

Mentions: WT mice fed a proatherogenic diet for 4 weeks showed a decrease in ACh-mediated vasodilatation compared with baseline values (baseline, 20% ± 3% change versus 4 weeks 9% ± 2% change; P <0.01) and WT age-matched mice on rodent chow (P <0.001). ACh-mediated vasodilatation in ABIN1[D485N]-chow (9% ± 2% change)-fed mice were significantly attenuated compared with values at baseline (P <0.001) and were significantly lower than age-matched WT mice on a chow diet (P <0.05) at 4 weeks, but were similar in magnitude to those observed in WT-cholesterol-fed mice (Figure 5A). Cholesterol feeding in ABIN1[D485N] mice further attenuated ACh-mediated vasodilatation (0.03% ± 0.03% change) compared with age-matched ABIN1[D485N]-chow-fed mice (P <0.001). ACh-mediated vasodilatation was significantly lower in ABIN1[D485N]-cholesterol-fed animals compared with WT-chow (P <0.001) and WT-cholesterol (P <0.001)-fed mice (Figure 5A).Figure 5


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.

Akbar N, Nanda S, Belch J, Cohen P, Khan F - Arthritis Res. Ther. (2015)

Follow-up vascular function. Microvascular responses at 4 weeks to (A) endothelium-dependent acetylcholine in WT-chow (n = 11), WT-cholesterol (n = 11), ABIN1[D485N]-chow (n = 10), and ABIN1[D485N]-cholesterol (n = 10)-fed mice; and (B) endothelium-independent sodium nitroprusside in the same mice (% change ± SEM). One-way ANOVA with post hoc Bonferroni correction. *P <0.05; **P <0.01; ***P <0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4342941&req=5

Fig5: Follow-up vascular function. Microvascular responses at 4 weeks to (A) endothelium-dependent acetylcholine in WT-chow (n = 11), WT-cholesterol (n = 11), ABIN1[D485N]-chow (n = 10), and ABIN1[D485N]-cholesterol (n = 10)-fed mice; and (B) endothelium-independent sodium nitroprusside in the same mice (% change ± SEM). One-way ANOVA with post hoc Bonferroni correction. *P <0.05; **P <0.01; ***P <0.001.
Mentions: WT mice fed a proatherogenic diet for 4 weeks showed a decrease in ACh-mediated vasodilatation compared with baseline values (baseline, 20% ± 3% change versus 4 weeks 9% ± 2% change; P <0.01) and WT age-matched mice on rodent chow (P <0.001). ACh-mediated vasodilatation in ABIN1[D485N]-chow (9% ± 2% change)-fed mice were significantly attenuated compared with values at baseline (P <0.001) and were significantly lower than age-matched WT mice on a chow diet (P <0.05) at 4 weeks, but were similar in magnitude to those observed in WT-cholesterol-fed mice (Figure 5A). Cholesterol feeding in ABIN1[D485N] mice further attenuated ACh-mediated vasodilatation (0.03% ± 0.03% change) compared with age-matched ABIN1[D485N]-chow-fed mice (P <0.001). ACh-mediated vasodilatation was significantly lower in ABIN1[D485N]-cholesterol-fed animals compared with WT-chow (P <0.001) and WT-cholesterol (P <0.001)-fed mice (Figure 5A).Figure 5

Bottom Line: The magnitude of attenuation was similar to that observed in WT-cholesterol-fed animals (versus WT-chow, P<0.01).IL-1α was significantly greater in all groups compared with WT-chow (P<0.01).These results suggest that the ABIN1-mediated hyperactivation of IKKs and MAPKs might mediate chronic inflammation and CVD development.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus