The role of lysyl oxidase family members in the stabilization of abdominal aortic aneurysms.
Abdominal aortic aneurysms (AAAs) are a major cause of morbidity and mortality in the United States today. We employed a model for AAA development using apolipoprotein E knock out mice fed a high-fat diet and treated with ANG II and β-aminopropionitrile (β-APN) for 4 wk. ANG II induces hypertension and atherosclerotic disease, whereas β-APN inhibits the activity of the lysyl oxidase/ lysyl oxidase-like protein (LOX/LOXL) family members. LOX/LOXL family members crosslink collagen and elastin in the extracellular matrix and therefore contribute to the integrity and stabilization of a healthy vessel wall. In this model, cotreatment with ANG II and β-APN caused a 90% AAA incidence and increased atherosclerotic lesion formation from less than 5% to greater than 25% after 4 wk. In more atheroprotected mouse strains (C57BL/6 and BalbC), cotreatment with ANG II and β-APN caused 50% and 40% AAA incidence, respectively. These data demonstrate the importance of LOX/LOXL to the stability of the vessel wall. Therapeutic strategies to overexpress LOX/LOXL enzymes or to support the crosslinking of soluble matrix proteins in a polymeric scaffold are a promising opportunity to achieve stabilization of AAAs.
Division of Cardiology Department of Medicine, Emory University School of Medicine Atlanta, Georgia 30322, USA.
Ebony Washington
EW
Remus
Robert E
RE
O'Donnell
Kathryn
K
Rafferty
Daiana
D
Weiss
Giji
G
Joseph
Katalin
K
Csiszar
Sheri F T
SF
Fong
W Robert
WR
Taylor
D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000629:Aminopropionitrile / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001012:Aorta, Abdominal / Q000201:enzymology*; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology*; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000201:enzymology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D001057:Apolipoproteins E; D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C077112:Lox protein, mouse; D000629:Aminopropionitrile; D000594:Amino Acid Oxidoreductases; C511777:LOXL3 protein, mouse; C482019:Loxl1 protein, mouse; C485601:Loxl2 protein, mouse; C432408:Loxl4 protein, mouse; D008249:Protein-Lysine 6-Oxidase