title: Pharmacological inhibitor of notch signaling stabilizes the progression of small abdominal aortic aneurysm in a mouse model.
abstract: BACKGROUND
  The progression of abdominal aortic aneurysm (AAA) involves a sustained influx of proinflammatory macrophages, which exacerbate tissue injury by releasing cytokines, chemokines, and matrix metalloproteinases. Previously, we showed that Notch deficiency reduces the development of AAA in the angiotensin II-induced mouse model by preventing infiltration of macrophages. Here, we examined whether Notch inhibition in this mouse model prevents progression of small AAA and whether these effects are associated with altered macrophage differentiation.
  
  
  RESULTS
  Treatment with pharmacological Notch inhibitor (DAPT [N-(N-[3,5-difluorophenacetyl]-L-alanyl)-S-phenylglycine t-butyl ester]) at day 3 or 8 of angiotensin II infusion arrested the progression of AAA in Apoe(-/-) mice, as demonstrated by a decreased luminal diameter and aortic width. The abdominal aortas of Apoe(-/-) mice treated with DAPT showed decreased expression of matrix metalloproteinases and presence of elastin precursors including tropoelastin and hyaluronic acid. Marginal adventitial thickening observed in the aorta of DAPT-treated Apoe(-/-) mice was not associated with increased macrophage content, as observed in the mice treated with angiotensin II alone. Instead, DAPT-treated abdominal aortas showed increased expression of Cd206-positive M2 macrophages and decreased expression of Il12-positive M1 macrophages. Notch1 deficiency promoted M2 differentiation of macrophages by upregulating transforming growth factor β2 in bone marrow-derived macrophages at basal levels and in response to IL4. Protein expression of transforming growth factor β2 and its downstream effector pSmad2 also increased in DAPT-treated Apoe(-/-) mice, indicating a potential link between Notch and transforming growth factor β2 signaling in the M2 differentiation of macrophages.
  
  
  CONCLUSIONS
  Pharmacological inhibitor of Notch signaling prevents the progression of AAA by macrophage differentiation-dependent mechanisms. The study also provides insights for novel therapeutic strategies to prevent the progression of small AAA.
authors.affiliation: Center for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Children's Hospital, The Ohio State University, Columbus, OH (J.C., S.N.K., V.G., C.P.H.).
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Center for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Children's Hospital, The Ohio State University, Columbus, OH (J.C., S.N.K., V.G., C.P.H.).
authors.forename: Sara N
authors.initials: SN
authors.lastname: Koenig
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA (H.S.K.).
authors.forename: Helena S
authors.initials: HS
authors.lastname: Kuivaniemi
authors.affiliation: Center for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Children's Hospital, The Ohio State University, Columbus, OH (J.C., S.N.K., V.G., C.P.H.) Department of Pediatrics, The Ohio State University, Columbus, OH (V.G., C.P.H.) Department of Molecular Genetics, The Ohio State University, Columbus, OH (V.G.).
authors.forename: Vidu
authors.initials: V
authors.lastname: Garg
authors.affiliation: Center for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Children's Hospital, The Ohio State University, Columbus, OH (J.C., S.N.K., V.G., C.P.H.) Department of Pediatrics, The Ohio State University, Columbus, OH (V.G., C.P.H.).
authors.forename: Chetan P
authors.initials: CP
authors.lastname: Hans
mesh_terms: D000368:Aged; D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004549:Elastin / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D018345:Mice, Knockout; D008875:Middle Aged; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D053781:Transforming Growth Factor beta2 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C509042:Tgfb2 protein, mouse; D053781:Transforming Growth Factor beta2; D000804:Angiotensin II; D003094:Collagen; D004549:Elastin; D020782:Matrix Metalloproteinases
keywords: Notch1; Tgfβ2; abdominal aortic aneurysm; macrophage differentiation