title: Locally applied leptin induces regional aortic wall degeneration preceding aneurysm formation in apolipoprotein E-deficient mice.
abstract: OBJECTIVE
  Leptin promotes atherosclerosis and vessel wall remodeling. As abdominal aortic aneurysm (AAA) formation involves tissue remodeling, we hypothesized that local leptin synthesis initiates and promotes this process.
  
  
  RESULTS
  Human surgical AAA walls were analyzed for antigen and mRNA levels of leptin and leptin receptor, as well as mRNA for matrix metalloproteinases (MMP)-9 and MMP-12. Leptin and leptin receptor antigen were evident in all AAAs, and leptin, MMP-9, and MMP-12 mRNA was increased relative to age-matched nondilated controls. To simulate in vivo local leptin synthesis, ApoE(-/-) mice were subjected to a paravisceral periaortic application of low-dose leptin. Leptin-treated aortas exhibited decreased transforming growth factor-β and increased MMP-9 mRNA levels 5 days after surgery, and leptin receptor mRNA was upregulated by day 28. Serial ultrasonography demonstrated accelerated regional aortic diameter growth after 28 days, correlating with local medial degeneration, increased MMP-9, MMP-12, and periadventitial macrophage clustering. Furthermore, the combination of local periaortic leptin and systemic angiotensin II administration augmented medial MMP-9 synthesis and aortic aneurysm size.
  
  
  CONCLUSIONS
  Leptin is locally synthesized in human AAA wall. Paravisceral aortic leptin in ApoE(-/-) mice induces local medial degeneration and augments angiotensin II-induced AAA, thus suggesting novel mechanistic links between leptin and AAA formation.
authors.affiliation: Division of Vascular and Endovascular Surgery, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Tao
authors.forename: Peng
authors.initials: P
authors.lastname: Yu
authors.forename: Binh T
authors.initials: BT
authors.lastname: Nguyen
authors.forename: Boaz
authors.initials: B
authors.lastname: Mizrahi
authors.forename: Naphtali
authors.initials: N
authors.lastname: Savion
authors.forename: Frank D
authors.initials: FD
authors.lastname: Kolodgie
authors.forename: Renu
authors.initials: R
authors.lastname: Virmani
authors.forename: Shuai
authors.initials: S
authors.lastname: Hao
authors.forename: C Keith
authors.initials: CK
authors.lastname: Ozaki
authors.forename: Jacob
authors.initials: J
authors.lastname: Schneiderman
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D003692:Delayed-Action Preparations; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D006801:Humans; D020738:Leptin / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014463:Ultrasonography
chemical_list: D001057:Apolipoproteins E; D003692:Delayed-Action Preparations; C515448:LEPR protein, human; D020738:Leptin; D012333:RNA, Messenger; D054411:Receptors, Leptin; D016212:Transforming Growth Factor beta; C515447:leptin receptor, mouse; D000804:Angiotensin II; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12