Locally applied leptin induces regional aortic wall degeneration preceding aneurysm formation in apolipoprotein E-deficient mice

Ming Tao, Peng Yu, Binh T. Nguyen, Boaz Mizrahi, Naphtali Savion, Frank D. Kolodgie, Renu Virmani, Shuai Hao, C. Keith Ozaki, Jacob Schneiderman

Research output: Contribution to journalArticlepeer-review

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. METHODS AND 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. CONCLUSION-: 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.

Original languageEnglish
Pages (from-to)311-320
Number of pages10
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume33
Issue number2
DOIs
StatePublished - Feb 2013

Keywords

  • abdominal aortic aneurysm
  • angiotensin II
  • leptin
  • transforming growth factor-β
  • vessel wall remodeling

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