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LOX-1 deficiency increases ruptured abdominal aortic aneurysm via thinning of adventitial collagen

Hypertension Research volume 46, pages 63–74 (2023)Cite this article

Abstract

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a key mediator of inflammation and plays an important role in the pathogenesis of atherosclerosis. Conversely, LOX-1 deficiency has been shown to decrease inflammation and atherosclerosis, both of which have been proposed to contribute to abdominal aortic aneurysm (AAA) pathogenesis. However, the role of LOX-1 in AAA pathogenesis remains unknown. Here, we investigated the effects of Olr1 (which encodes LOX-1) deletion on angiotensin II (Ang II)-induced AAA in apolipoprotein E knockout (ApoE KO) mice to determine whether LOX-1 deficiency mitigates AAA development. To accomplish this, we used serial, non-invasive ultrasound assessment, which revealed that the incidence and expansion rate of AAA were similar regardless of Olr1 deletion. However, Olr1 deletion significantly increased severe AAAs, including ruptured AAAs resulting in death. Oil Red O staining of the harvested aortas showed that the extent of atheroma burden localized in aneurysmal lesions did not differ between LOX-1-deficient and control mice, suggesting that Olr1 deletion did not decrease atheroma burden in the aneurysmal wall. Further histopathological analysis revealed that aneurysmal lesions in LOX-1-deficient mice had fewer fibroblasts and myofibroblasts, as well as thinner adventitial collagen, although the degree of elastin fragmentation or disruption was similar between LOX-1-deficient and control mice. An in vitro study confirmed that the proliferation of adventitial fibroblasts collected from LOX-1-deficient mice was significantly attenuated despite Ang II stimulation. In conclusion, Olr1 deletion may not mitigate aneurysm development but rather increases the vulnerability of rupture by suppressing adventitial fibroblast proliferation and collagen synthesis.

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Acknowledgements

We thank the staff of the Division of Analytical Bio-Medicine and the Division of Laboratory Animal Research of the Advanced Research Support Center (ADRES), Ehime University for animal care and the preparation of histological specimens. We are also grateful to Itsuki Miyake from the Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University, for the support with blood pressure measurements.

Funding

This work was supported by a grant from the Setsuro Fujii Memorial, Osaka Foundation for the Promotion of Fundamental Medical Research (to KT).

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Authors and Affiliations

  1. Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Toon, Ehime, 7910295, Japan

    Kayo Takahashi, Jun Aono, Yasuhisa Nakao, Mika Hamaguchi, Chika Suehiro, Katsuji Inoue, Shuntaro Ikeda, Jun Suzuki & Osamu Yamaguchi

  2. Department of Pathology, Ehime University Graduate School of Medicine and Ehime University Proteo-Science Center, Toon, Ehime, 7910295, Japan

    Mie Kurata

  3. Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Ehime, Toon, Ehime, 7910295, Japan

    Tomohisa Sakaue

  4. Department of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Toon, Ehime, 7910295, Japan

    Tomohisa Sakaue

  5. Department of Molecular Pathophysiology, School of Medicine, Shinshu University, Matsumoto, Nagano, 3908621, Japan

    Akemi Kakino & Tatsuya Sawamura

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  1. Kayo Takahashi
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Correspondence to Jun Aono.

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Takahashi, K., Aono, J., Nakao, Y. et al. LOX-1 deficiency increases ruptured abdominal aortic aneurysm via thinning of adventitial collagen. Hypertens Res 46, 63–74 (2023). https://doi.org/10.1038/s41440-022-01093-x

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