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

Clin Sci (Lond). 2015 May;128(9):559-65. doi: 10.1042/CS20140696.

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 β-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopropionitrile
  • Angiotensin II
  • Animals
  • Aorta, Abdominal / drug effects*
  • Aorta, Abdominal / enzymology
  • Aortic Aneurysm, Abdominal / chemically induced
  • Aortic Aneurysm, Abdominal / enzymology
  • Aortic Aneurysm, Abdominal / prevention & control*
  • Aortic Rupture / enzymology
  • Aortic Rupture / prevention & control
  • Cells, Cultured
  • Cytoprotection
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress / drug effects
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride
  • Extracellular Matrix / metabolism
  • Humans
  • Interleukin-6 / metabolism
  • Male
  • Mice, Inbred C57BL
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / enzymology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / enzymology
  • Oxidative Stress / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Quinazolines / pharmacology*
  • Rats, Sprague-Dawley
  • Time Factors

Substances

  • Interleukin-6
  • Protein Kinase Inhibitors
  • Quinazolines
  • Angiotensin II
  • Aminopropionitrile
  • Erlotinib Hydrochloride
  • EGFR protein, human
  • EGFR protein, mouse
  • Egfr protein, rat
  • ErbB Receptors