Chika Suehiro1, Jun Suzuki2, Mika Hamaguchi1, Kayo Takahashi1, Tomoaki Nagao1, Tomoki Sakaue3, Teruyoshi Uetani1, Jun Aono1, Shuntaro Ikeda1, Takafumi Okura3, Haruki Okamura4, Osamu Yamaguchi1. 1. Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Toon, Ehime, 7910295, Japan. 2. Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Toon, Ehime, 7910295, Japan. Electronic address: junbell@m.ehime-u.ac.jp. 3. Department of Community and Emergency Medicine, Ehime University Graduate School of Medicine, Toon, Ehime, 7910295, Japan. 4. Laboratory of Tumor Immunology and Cell Therapy, Hyogo College of Medicine, Nishinomiya, Hyogo, 6638501, Japan.
Abstract
BACKGROUND AND AIMS: Abdominal aortic aneurysm (AAA) is a common disease; however, its exact pathogenesis remains unknown, and no specific medical therapies are available. Interleukin (IL)-18 plays a crucial role in atherosclerotic plaque destabilization and is a strong predictor of cardiovascular death. Here, we investigated the role of IL-18 in AAA pathogenesis using an experimental mouse model. METHODS AND RESULTS: After infusion of angiotensin II (Ang II) for 4 weeks and β-aminopropionitrile (BAPN) for 2 weeks, 58% of C57/6J wild-type (WT) mice developed AAA associated with enhanced expression of IL-18; however, disease incidence was significantly lower in IL-18-/- mice than in WT mice (p < 0.01), although no significant difference was found in systolic blood pressure between WT mice and IL-18-/- mice in this model. Additionally, IL-18 deletion significantly attenuated Ang II/BAPN-induced macrophage infiltration, macrophage polarization into inflammatory M1 phenotype, and matrix metalloproteinase (MMP) activation in abdominal aortas, which is associated with reduced expression of osteopontin (OPN). CONCLUSIONS: These findings indicate that IL-18 plays an important role in the development of AAA by enhancing OPN expression, macrophage recruitment, and MMP activation. Moreover, IL-18 represents a previously unrecognized therapeutic target for the prevention of AAA formation.
BACKGROUND AND AIMS: Abdominal aortic aneurysm (AAA) is a common disease; however, its exact pathogenesis remains unknown, and no specific medical therapies are available. Interleukin (IL)-18 plays a crucial role in atherosclerotic plaque destabilization and is a strong predictor of cardiovascular death. Here, we investigated the role of IL-18 in AAA pathogenesis using an experimental mouse model. METHODS AND RESULTS: After infusion of angiotensin II (Ang II) for 4 weeks and β-aminopropionitrile (BAPN) for 2 weeks, 58% of C57/6J wild-type (WT) mice developed AAA associated with enhanced expression of IL-18; however, disease incidence was significantly lower in IL-18-/- mice than in WT mice (p < 0.01), although no significant difference was found in systolic blood pressure between WT mice and IL-18-/- mice in this model. Additionally, IL-18 deletion significantly attenuated Ang II/BAPN-induced macrophage infiltration, macrophage polarization into inflammatory M1 phenotype, and matrix metalloproteinase (MMP) activation in abdominal aortas, which is associated with reduced expression of osteopontin (OPN). CONCLUSIONS: These findings indicate that IL-18 plays an important role in the development of AAA by enhancing OPN expression, macrophage recruitment, and MMP activation. Moreover, IL-18 represents a previously unrecognized therapeutic target for the prevention of AAA formation.
Authors: Philipp Jud; Nicolas Verheyen; Martin H Stradner; Christian Dejaco; Dieter Szolar; René Thonhofer; Leyla Schweiger; Marianne Brodmann; Franz Hafner Journal: Rheumatol Int Date: 2022-08-23 Impact factor: 3.580
Authors: Hisashi Sawada (澤田悠); Hong S Lu (吕红); Lisa A Cassis; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2022-01-20 Impact factor: 8.311