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

Kikuo Isoda, Koji Akita, Kenichi Kitamura, Yayoi Sato-Okabayashi, Tomoyasu Kadoguchi, Sarasa Isobe, Fumie Ohtomo, Motoaki Sano, Kazunori Shimada, Yoichiro Iwakura, Hiroyuki Daida

Research output: Contribution to journalArticle

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Abstract

Background: 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. Methods and results: 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. Conclusions: 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.

Original languageEnglish
JournalInternational Journal of Cardiology
DOIs
Publication statusAccepted/In press - 2018 Jan 1

Fingerprint

Aortic Aneurysm
Interleukin-1
Interleukin-1 Receptors
Angiotensin II
Inflammation
Abdominal Aortic Aneurysm
Blood Pressure
Aortic Rupture
Abdominal Aorta
Hypertension

Keywords

  • Aneurysm
  • Angiotensin II
  • Anti-IL-1β antibody
  • Hypertension
  • IL-1 receptor antagonist
  • Inflammation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Isoda, K., Akita, K., Kitamura, K., Sato-Okabayashi, Y., Kadoguchi, T., Isobe, S., ... Daida, H. (Accepted/In press). Inhibition of interleukin-1 suppresses angiotensin II-induced aortic inflammation and aneurysm formation. International Journal of Cardiology. https://doi.org/10.1016/j.ijcard.2018.05.072

Inhibition of interleukin-1 suppresses angiotensin II-induced aortic inflammation and aneurysm formation. / Isoda, Kikuo; Akita, Koji; Kitamura, Kenichi; Sato-Okabayashi, Yayoi; Kadoguchi, Tomoyasu; Isobe, Sarasa; Ohtomo, Fumie; Sano, Motoaki; Shimada, Kazunori; Iwakura, Yoichiro; Daida, Hiroyuki.

In: International Journal of Cardiology, 01.01.2018.

Research output: Contribution to journalArticle

Isoda, K, Akita, K, Kitamura, K, Sato-Okabayashi, Y, Kadoguchi, T, Isobe, S, Ohtomo, F, Sano, M, Shimada, K, Iwakura, Y & Daida, H 2018, 'Inhibition of interleukin-1 suppresses angiotensin II-induced aortic inflammation and aneurysm formation', International Journal of Cardiology. https://doi.org/10.1016/j.ijcard.2018.05.072
Isoda, Kikuo ; Akita, Koji ; Kitamura, Kenichi ; Sato-Okabayashi, Yayoi ; Kadoguchi, Tomoyasu ; Isobe, Sarasa ; Ohtomo, Fumie ; Sano, Motoaki ; Shimada, Kazunori ; Iwakura, Yoichiro ; Daida, Hiroyuki. / Inhibition of interleukin-1 suppresses angiotensin II-induced aortic inflammation and aneurysm formation. In: International Journal of Cardiology. 2018.
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abstract = "Background: 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. Methods and results: 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. Conclusions: 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.",
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AU - Akita, Koji

AU - Kitamura, Kenichi

AU - Sato-Okabayashi, Yayoi

AU - Kadoguchi, Tomoyasu

AU - Isobe, Sarasa

AU - Ohtomo, Fumie

AU - Sano, Motoaki

AU - Shimada, Kazunori

AU - Iwakura, Yoichiro

AU - Daida, Hiroyuki

PY - 2018/1/1

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N2 - Background: 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. Methods and results: 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. Conclusions: 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.

AB - Background: 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. Methods and results: 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. Conclusions: 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.

KW - Aneurysm

KW - Angiotensin II

KW - Anti-IL-1β antibody

KW - Hypertension

KW - IL-1 receptor antagonist

KW - Inflammation

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