Abstract 16562: Peri-Aortic Leptin Augments the Aneurysmogenic Effect of Angiotensin II in Apolipoprotein E Deficient Mice
Background: Leptin functions as a proatherogenic hormone capable of inciting vessel wall remodeling mechanisms. We thus hypothesized that Ang II drives leptin generation by SMCs, and that leptin accelerates aneurysmogenesis in the Ang II murine aneurysm model.
Methods: Male ApoE -/- mice underwent laparotomy for local perivisceral aortic application of leptin (50μ g) via slow release gel (n=14). Control mice received placebo gel (n=14). All mice received Ang II via minipump (1000ng/kg/day) and a high fat diet. Aortic diameter at the abdomen and arch were examined periodically by ultrasound (US; VisualSonic 2100). Additional endpoints included microscopic morphometry, and immunohistochemistry for leptin, leptin receptor (ObR), MMP-9, and Mac3. Leptin release from the gel construct was studied in vitro, and systemic leptin levels determined. Cultured human aortic SMCs from AAA explants were exposed to Ang II (10 -5 M) (+/- receptor blocker) to investigate leptin induction, and human AAA wall specimens were assessed for leptin and ObR antigen.
Results: Excessive leptin at the aortic perivisceral region enhanced the process of Ang II related aneurysmogenesis. This was evident by US assessing perivisceral aortic growth rate (p=0.069), and via morphometry of the corresponding aortic lumen. US correlated with histological measurements (p=0.001). Lethal rupture of arch aneurysm occurred in 43% of leptin, and 50% of control mice (p=NS). Leptin antigen was demonstrated in medial SMCs and macrophages of aneurysmal segments in both groups. Leptin treated mice exhibited increased ObR immunoreactivity, augmented MMP-9 antigen in medial SMCs, and increased macrophage accumulation in the perivisceral aortic. Kinetic studies revealed leptin release from the gel for at least 21 days; however, systemic leptin was not elevated. Ang II induced human AAA SMC leptin synthesis by via T1 receptor. Leptin, and ObR antigen were abundantly present and generally co-localized to SMCs and macrophages of AAA wall specimens.
Conclusions: Ang II related aneurysmogenesis in ApoE-/- mice may involve leptin induction at the aortic wall. Locally induced aortic wall leptin may play a role in human AAA genesis.
- © 2011 by American Heart Association, Inc.