Epidermal growth factor receptor inhibitor protects against abdominal aortic aneurysm in a mouse model

Takashi Obama, Toshiyuki Tsuji, Tomonori Kobayashi, Yamato Fukuda, Takehiko Takayanagi, Yoshinori Taro, Tatsuo Kawai, Steven J. Forrester, Katherine J. Elliott, Eric Choi, Alan Daugherty, Victor Rizzo, Satoru Eguchi

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Angiotensin II (Ang II) has been implicated in the development of abdominal aortic aneurysm (AAA). In vascular smooth muscle cells (VSMC), Ang II activates epidermal growth factor receptor (EGFR) mediating growth promotion. We hypothesized that inhibition of EGFR prevents Ang II-dependent AAA. C57BL/6 mice were co-treated with Ang II and ß-aminopropionitrile (BAPN) to induce AAA with or without treatment with EGFR inhibitor, erlotinib. Without erlotinib, 64.3% of mice were dead due to aortic rupture. All surviving mice had AAA associated with EGFR activation. Erlotinib-treated mice did not die and developed far fewer AAA. The maximum diameters of abdominal aortas were significantly shorter with erlotinib treatment. In contrast, both erlotinib-treated and non-treated mice developed hypertension. The erlotinib treatment of abdominal aorta was associated with lack of EGFR activation, endoplasmic reticulum (ER) stress, oxidative stress, interleukin-6 induction and matrix deposition. EGFR activation in AAA was also observed in humans. In conclusion, EGFR inhibition appears to protect mice from AAA formation induced by Ang II plus BAPN. The mechanism seems to involve suppression of vascular EGFR and ER stress.

Original languageEnglish
Pages (from-to)559-565
Number of pages7
JournalClinical Science
Volume128
Issue number9
DOIs
StatePublished - 2015

Bibliographical note

Publisher Copyright:
© 2015 Biochemical Society.

Keywords

  • Abdominal aortic aneurysm
  • Angiotensin II
  • Endoplasmic reticulum stress
  • Hypertension
  • Rupture
  • Signal transduction

ASJC Scopus subject areas

  • Medicine (all)

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