Inhibition of interleukin-1 suppresses angiotensin II-induced aortic inflammation and aneurysm formation

• Published in: International journal of cardiology Vol. 270; pp. 221 - 227
• Main Authors: Isoda, Kikuo, Akita, Koji, Kitamura, Kenichi, Sato-Okabayashi, Yayoi, Kadoguchi, Tomoyasu, Isobe, Sarasa, Ohtomo, Fumie, Sano, Motoaki, Shimada, Kazunori, Iwakura, Yoichiro, Daida, Hiroyuki
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2018
• Subjects: Aneurysm; Angiotensin II; Angiotensin II - toxicity; Animals; Anti-IL-1β antibody; Aortic Aneurysm, Abdominal - drug therapy; Aortic Aneurysm, Abdominal - metabolism; Aortic Aneurysm, Abdominal - pathology; Blood Pressure - drug effects; Blood Pressure - physiology; Heart Rate - drug effects; Heart Rate - physiology; Hypertension; IL-1 receptor antagonist; Immunoglobulin G - pharmacology; Immunoglobulin G - therapeutic use; Immunologic Factors - pharmacology; Immunologic Factors - therapeutic use; Inflammation; Interleukin 1 Receptor Antagonist Protein - antagonists & inhibitors; Interleukin 1 Receptor Antagonist Protein - metabolism; Interleukin-1beta - antagonists & inhibitors; Interleukin-1beta - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Vasculitis - chemically induced; Vasculitis - metabolism; Vasculitis - pathology; Hypertension; Anti-IL-1β antibody; Inflammation; Angiotensin II; IL-1 receptor antagonist; Aneurysm
• ISSN: 0167-5273; 1874-1754
• DOI: 10.1016/j.ijcard.2018.05.072

Angiotensin II (Ang II) activates components of the inflammatory cascade, which promotes hypertension and development of abdominal aortic aneurysm (AAA). This study aimed to elucidate the effects of an IL-1 receptor antagonist (IL-1Ra) and an anti-IL-1β antibody (01BSUR) on Ang II-induced AAA. Male wild-type (WT) and IL-1Ra-deficient (IL-1Ra−/−) mice were infused with Ang II (1000 ng/kg/min) using subcutaneous osmotic pumps for 28 days. Fourteen days post-infusion, both systolic blood pressure (SBP) (Ang II-treated IL-1Ra−/−:149 ± 2 vs. Ang II-treated WT:126 ± 3 mm Hg, p < 0.001) and abdominal aortic width (0.94 ± 0.09 vs. 0.49 ± 0.03 mm, p < 0.001) were significantly higher in IL-1Ra−/− mice than in WT mice. Because 28-day infusion with Ang II in IL-1Ra−/− mice significantly increased the occurrence of fatal aortic rupture (89% vs. 6%, p < 0.0001), both types of mice were infused with Ang II for only 14 days, and histological analyses were performed at 28 days. Interestingly, AAA increased more significantly in IL-1Ra−/− mice than in WT mice (p < 0.001), although SBP did not differ at 28 days in IL-1Ra−/− and WT mice (117 ± 4 vs. 115 ± 3 mm Hg, p = 0.71 (after cessation of Ang II infusion)). Histological analyses showed numerous inflammatory cells around the abdominal aorta in IL-1Ra−/− mice, but not in WT mice. Finally, compared with IgG2a treatment, treatment with 01BSUR decreased Ang II-induced AAA in IL-1Ra−/− mice. The present study demonstrates that inhibition of IL-1β significantly suppresses AAA formation after Ang II infusion, suggesting that suppression of IL-1β may provide an additional strategy to protect against AAA in hypertensive patients. •IL-1Ra deficiency promotes proinflammatory cytokines and MMP production after Ang II stimulation.•IL-1Ra deficiency promotes aortic aneurysm formation after Ang II stimulation.•Treatment with an anti-IL-1β antibody suppresses Ang II-induced aortic inflammation.•Treatment with an anti-IL-1β antibody suppresses Ang II-induced aortic aneurysm.•This study highlights the potential therapeutic benefit of anti-IL-1β therapy in preventing aortic aneurysm.