Abstract 100: Periaortic Leptin Induces Local Medial Degeneration in ApoE-/- Mice Preceding Aneurysm Formation
Background: Leptin (Ob) is a proatherogenic hormone involved in vessel wall remodeling. We hypothesized that Ob locally synthesized in the abdominal aorta regulates vascular remodeling mediators (TGFβ, MMPs) thereby sensitizing the aorta to subsequent aneurysm formation.
Methods: Human abdominal aortic aneurysm (AAA) wall (n=10), and non-dilated aortic (n=3) samples underwent real time qPCR mRNA analysis for Ob and Ob receptor (ObR), and immunohistochemical analysis (SM-αactin, CD68, Ob, and ObR). Plasma samples obtained prior to AAA surgery were analyzed for Ob and ObR antigen (n=20). A novel mouse model was utilized to elucidate the role of Ob in AAA formation. Local Ob synthesis was simulated by point application of 20μg Ob slow release (n=10), or placebo (n=10) compound at the peri-vascular space of the para-visceral aorta in ApoE-/- mice on a Western diet. Serial ultrasound examinations on days 0, 14, 28, 35, and 42 assessed aortic diameter at reference locations. A parallel group (n=10), randomized to Ob or placebo treatment was euthanized on day 5 for aortic mRNA analysis.
Results: Increased Ob mRNA levels and immunoreactivity were evident in human AAA wall samples vs controls. Plasma Ob and ObR levels were within normal range. Ob treated mice demonstrated augmented growth rate of luminal aortic diameter in the para-visceral segment on day 28 (p=0.0001). Aortas analyzed 5 days after Ob deployment revealed suppressed TGFβ mRNA (p=0.002), while MMP-9 transcript was up-regulated (p=0.047). Ob treated mice euthanized on day 45 demonstrated localized aortic derangement of elastic fibers and loss of SM-αActin (p=0.07), alongside with increased MMP-9 (p=0.02), MMP-12 (p=0.001) antigen, and augmented adventitial macrophage infiltration.
Conclusions: Ob is locally synthesized in human AAA wall. Peri-aortic Ob modulates the vessel wall in ApoE-/- mice, inducing medial degeneration at the para-visceral region. Mechanistically, the observed derangement of ECM components was associated with suppressed TGFβ mRNA, and up-regulated MMP-9 synthesis. These data suggest novel mechanistic links between Ob and human AAA formation.
- © 2012 by American Heart Association, Inc.