title: Epidermal growth factor receptor inhibitor protects against abdominal aortic aneurysm in a mouse model.
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.
authors.affiliation: *Cardiovascular Research Center, Temple University School of Medicine, Philadelphia PA 19140, U.S.A.
authors.forename: Takashi
authors.initials: T
authors.lastname: Obama
authors.affiliation: *Cardiovascular Research Center, Temple University School of Medicine, Philadelphia PA 19140, U.S.A.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tsuji
authors.affiliation: *Cardiovascular Research Center, Temple University School of Medicine, Philadelphia PA 19140, U.S.A.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: *Cardiovascular Research Center, Temple University School of Medicine, Philadelphia PA 19140, U.S.A.
authors.forename: Yamato
authors.initials: Y
authors.lastname: Fukuda
authors.affiliation: *Cardiovascular Research Center, Temple University School of Medicine, Philadelphia PA 19140, U.S.A.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Takayanagi
authors.affiliation: *Cardiovascular Research Center, Temple University School of Medicine, Philadelphia PA 19140, U.S.A.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Taro
authors.affiliation: *Cardiovascular Research Center, Temple University School of Medicine, Philadelphia PA 19140, U.S.A.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kawai
authors.affiliation: *Cardiovascular Research Center, Temple University School of Medicine, Philadelphia PA 19140, U.S.A.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Forrester
authors.affiliation: *Cardiovascular Research Center, Temple University School of Medicine, Philadelphia PA 19140, U.S.A.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Elliott
authors.affiliation: †Department of Surgery, Temple University School of Medicine, Philadelphia PA 19140, U.S.A.
authors.forename: Eric
authors.initials: E
authors.lastname: Choi
authors.affiliation: ‡Saha Cardiovascular Research Center, University of Kentucky, Lexington KY 40536, U.S.A.
authors.forename: Alan
authors.initials: A
authors.lastname: Daugherty
authors.affiliation: *Cardiovascular Research Center, Temple University School of Medicine, Philadelphia PA 19140, U.S.A.
authors.forename: Victor
authors.initials: V
authors.lastname: Rizzo
authors.affiliation: *Cardiovascular Research Center, Temple University School of Medicine, Philadelphia PA 19140, U.S.A.
authors.forename: Satoru
authors.initials: S
authors.lastname: Eguchi
mesh_terms: D000629:Aminopropionitrile; D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000201:enzymology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D001019:Aortic Rupture / Q000201:enzymology / Q000517:prevention & control; D002478:Cells, Cultured; D019610:Cytoprotection; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000804:Angiotensin II; D000629:Aminopropionitrile; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; C541485:EGFR protein, mouse; C483803:Egfr protein, rat; D066246:ErbB Receptors