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

doi:10.1016/j.ijcard.2018.05.072

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

Int J Cardiol. 2018 Nov 1:270:221-227. doi: 10.1016/j.ijcard.2018.05.072. Epub 2018 Jun 6.

Affiliations

¹ Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan. Electronic address: kisoda@juntendo.ac.jp.
² Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Hongo, Bunkyo-ku, Tokyo, Japan.
³ Division of Cardiology, Keio University, Shinanomachi, Shinjuku-ku, Tokyo, Japan.
⁴ Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan.

PMID: 29884291
DOI: 10.1016/j.ijcard.2018.05.072

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.

Keywords: Aneurysm; Angiotensin II; Anti-IL-1β antibody; Hypertension; IL-1 receptor antagonist; Inflammation.

MeSH terms

Angiotensin II / toxicity*
Animals
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
Immunoglobulin G / pharmacology
Immunoglobulin G / therapeutic use
Immunologic Factors / pharmacology
Immunologic Factors / therapeutic use
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

Substances

Il1rn protein, mouse
Immunoglobulin G
Immunologic Factors
Interleukin 1 Receptor Antagonist Protein
Interleukin-1beta
Angiotensin II