Abstract 12140: Beneficial Effects of Heme Oxygenase-1 Expression and Activity in Experimental Abdominal Aortic Aneurysm
The cytoprotective enzyme, heme oxygenase-1 (HO-1) is expressed in several vascular cell types, including macrophages. We hypothesized that HO-1 attenuates macrophage activation and inhibits abdominal aortic aneurysm (AAA) formation. Wild-type (WT, HO-1+/+, n=14) or HO-1 heterozygous (HO-1+/−, n=13) FVB mice were subjected to aortic elastase perfusion to induce experimental AAAs. AAA progression was monitored weekly by ultrasonography. At days 7 and 28 post-AAA induction, mice were euthanized for histological analyses. Expression of inflammatory cytokines and chemokines were assessed by qRT-PCR in thioglycollate-elicited macrophages from WT and HO-1+/− mice (n=5 for each group). The abdominal aortic diameter was significantly increased in HO-1+/− mice compared to WT mice after elastase perfusion (Figure1). HO-1+/− mice also had increased tissue macrophages at day 7 (310.6±4.2 vs 179.5±6.2 cells/high-power field [hpf], p<0.001) and at day 28 (231.1±27.6 vs 43.0±8.9 cells/hpf, p<0.001) as compared with WT mice. Induction of HO activity in HO-1+/− mice (n=7) by IP injections of heme (60 mM/g/2 wks) diminished AAA formation to a level similar to WT mice (p<0.001) and resulted in a macrophage infiltrate reduction of 25% (53.1 ±9.6 cells/hpf, p< 0.001) at day 28 relative to untreated HO-1+/− mice (Figure1). In addition, thioglycollate-elicited peritoneal macrophages from HO-1+/− mice exhibited increased expression of the proinflammatory cytokines MCP1, TNF-a, IL-1b and IL-6 (4.7-, 2.0-, 3.1- and 2.3-fold, p<0.05, respectively). Meanwhile mRNA levels of anti-inflammatory cytokines IL-10 and TGF-b1 were reduced in HO-1+/− mice (0.47- and 0.61-fold, p<0.05, respectively). In conclusion, Induction of HO-1 activity significantly reduces AAA formation in the elastase model of experimental AAA disease. The underlying mechanism appears in part to be mediated by a reduction of the local activation of macrophages in the aneurismal site.
- © 2010 by American Heart Association, Inc.