Deletion of progranulin exacerbates atherosclerosis in ApoE knockout mice

Ryota Kawase, Tohru Ohama, Akifumi Matsuyama, Takashi Matsuwaki, Takeshi Okada, Taiji Yamashita, Miyako Yuasa-Kawase, Hajime Nakaoka, Kazuhiro Nakatani, Miwako Inagaki, Kazumi Tsubakio-Yamamoto, Daisaku Masuda, Yumiko Nakagawa-Toyama, Makoto Nishida, Yasukazu Ohmoto, Masugi Nishihara, Issei Komuro, Shizuya Yamashita

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Abstract

Aims: Progranulin (PGRN) is a multifunctional protein known to be involved in inflammation. However, the relation between PGRN and atherosclerosis remains elusive. The aim of this study was to define the role of PGRN in the development of atherosclerosis. Methods and results: First, we checked the expression levels of PGRN in human atherosclerotic plaques. Immunohistochemical analysis showed that PGRN is strongly expressed in foam cells of atherosclerotic plaques. Wealso found that PGRN is expressed more abundantly in macrophages than in the smooth muscle cells of atherosclerotic lesions in ApoE-/- mice fed a high-fat diet for 12 weeks. Next, PGRN-/-ApoE-/- mice were generated to investigate the effect of PGRN on the development of atherosclerosis. PGRN-/-ApoE-/- mice exhibited severe atherosclerotic lesions compared with PGRN+/+ApoE-/- mice, despite their anti-atherogenic lipid profile. These resultsare partly duetoenhanced expression of inflammatory cytokines, adhesion molecules, and decreased expression of endothelial nitric oxide synthase. In addition, lack of PGRN leads to accumulate excessive cholesterol in the macrophages and alter HDL-associated proteins. Conclusion: PGRN seems to be involved in the pathogenesis of atherosclerosis, possibly by various anti-atherogenic effects, including modulation of local and/or systemic inflammation.

Original languageEnglish
Pages (from-to)125-133
Number of pages9
JournalCardiovascular Research
Volume100
Issue number1
DOIs
Publication statusPublished - 01-10-2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Kawase, R., Ohama, T., Matsuyama, A., Matsuwaki, T., Okada, T., Yamashita, T., Yuasa-Kawase, M., Nakaoka, H., Nakatani, K., Inagaki, M., Tsubakio-Yamamoto, K., Masuda, D., Nakagawa-Toyama, Y., Nishida, M., Ohmoto, Y., Nishihara, M., Komuro, I., & Yamashita, S. (2013). Deletion of progranulin exacerbates atherosclerosis in ApoE knockout mice. Cardiovascular Research, 100(1), 125-133. https://doi.org/10.1093/cvr/cvt178