A highly selective mPGES-1 inhibitor to block abdominal aortic aneurysm progression in the angiotensin mouse model

Abstract

Abdominal aortic aneurysm (AAA) is a deadly, permanent ballooning of the aortic artery. Pharmacological and genetic studies have pointed to multiple proteins, including microsomal prostaglandin E₂ synthase-1 (mPGES-1), as potentially promising targets. However, it remains unknown whether administration of an mPGES-1 inhibitor can effectively attenuate AAA progression in animal models. There are still no FDA-approved pharmacological treatments for AAA. Current research stresses the importance of both anti-inflammatory drug targets and rigor of translatability. Notably, mPGES-1 is an inducible enzyme responsible for overproduction of prostaglandin E₂ (PGE₂)-a well-known principal pro-inflammatory prostanoid. Here we demonstrate for the first time that a highly selective mPGES-1 inhibitor (UK4b) can completely block further growth of AAA in the ApoE-/- angiotensin (Ang)II mouse model. Our findings show promise for the use of a mPGES-1 inhibitor like UK4b as interventional treatment of AAA and its potential translation into the clinical setting.

Keywords: Abdominal aortic aneurysm; Aneurysm; Anti-inflammation; Prostaglandin E2; mPGES-1 inhibitor.

Figure 1

AAA progression in 8-week-old and 12-week-old mice. (A) Abdominal aortic diameter from day 0 to day 28 of AngII infusion. Mean ± SEM; n = 10 (8-weeks-old), n = 10 (12-weeks-old). *P < 0.05, ## **P < 0.01, #### **** P < 0.0001. Significance inter-group overall effect (*) by paired t-test (P = 0.0078). Significance intra-group versus day 0 (*) by two-way ANOVA. Significance inter-group each day (#) by two-way ANOVA. (B) Abdominal aortic diameter at day 28 of 8-week-old (8 weeks) and 12-week-old (12 weeks) mice. Mean ± SEM; n = 8 (8 weeks), n = 4 (12 weeks); * P < 0.05 (P = 0.0417) by unpaired t-test.

Figure 2

AAA progression in AngII only control mice and UK4b treated mice with administration started day 7. (A) Abdominal aortic diameter from day 0 to day 28 of AngII infusion. Mean ± SEM; n = 14 for control group in which one mouse died before day 7 and one mouse died after day 7, n = 6 for the 10 mg/kg group which one mouse died before day 7, n = 8 for the 20 mg/kg group in which one mouse died before day 7; *P < 0.05, **P < 0.01. Significance inter-group overall by one-way ANOVA (P = 0.0045 [control v 10], P = 0.0029 [control v 20], P = 0.6860 [10 v 20). Significance intra-group day 0 versus day 7 by two-way ANOVA (P = 0.0002 [control], P = 0.0018 [10], P = 0.0047 [20]). Significance intra-group day 7 versus day 28 by two-way ANOVA (P = 0.0046 [control], P = 0.4443 [10], P = 0.8842 [20]). (B) Abdominal aortic diameter on day 14. Mean ± SEM; n = 12 (control), n = 5 (10 mg/kg), n = 8 (20 mg/kg). (C) Abdominal aortic diameter on day 21. Mean ± SEM; n = 12 (control), n = 5 (10 mg/kg), n = 7 (20 mg/kg); *P < 0.05 (P = 0.0441 [control v 20]) by one-way ANOVA. (D) Abdominal aortic diameter on day 28. Mean ± SEM; n = 12 (control), n = 5 (10 mg/kg), n = 7 (20 mg/kg); *P < 0.05 (P = 0.0361 [control v 10], P = 0.0213 [control v 20]) by one-way ANOVA. (E) Average abdominal aortic diameter from day 14 through day 28. Mean ± SEM; n = 12 (control), n = 5 (10 mg/kg), n = 7 (20 mg/kg); **P < 0.01, ***P < 0.001 (P = 0.0069 [control v 10], P = 0.0008 [control v 20]) by one-way ANOVA.

Figure 3

Correlation of final abdominal aortic diameter measurements by in vivo ultrasonography and ex vivo tissue for each mouse (all groups). Linear regression graphed with 95% CI. n = 20; ****P < 0.0001 by Pearson r correlation and linear regression analysis.

Figure 4

The change in maximal abdominal aortic diameter versus the change in plasma PGE₂ between day 0–7 and day 7–28 (all groups). Linear regression graphed with 95% CI. n = 8; *P < 0.05 (P = 0.042) by Pearson r correlation and linear regression analysis.

Figure 5

Plasma concentration of IL-1α at day 0, 7, and 28 in control and drug treated mice. Mean ± SEM; n = 9 (control day 0), n = 5 (control day 7), n = 8 (control day 28), n = 7 (UK4b day 0), n = 8 (UK4b day 7), n = 13 (UK4b day 28); **P < 0.01 (P = 0.0021 [control day 0 v day 28], P = 0.0038 [control day 7 v day 28], P = 0.0012 [UK4b v control]) by two-way ANOVA.

Figure 6

Representative ex vivo aortic tissues on day 28 in the three groups. Tissues were chosen as those that best represented the consistent pathology seen in each group. (A) Control, (B) UK4b 10 mg/kg, (C) UK4b 20 mg/kg.

Figure 7

Tissue histology of mouse abdominal aorta at the maximum width: (A–C) H&E, (D–F) VVG, and (G–I) Masson’s Trichrome. Treatments: (A, D, G) control, (B, E, H) UK4b 10 mg/kg, and (C, F, I) UK4b 20 mg/kg.