Abstract 17207: The Role Of Ciap2 In Atherosclerotic Lesion Developmen
Background: Macrophages play a key role in the development of atherosclerotic lesions. The net effect of early lesional macrophage apoptosis is modulation of lesion cellularity and decreased lesion progression. Cellular Inhibitor of Apoptosis 2 (cIAP2) belongs to the IAP gene family, the only recognized group of endogenous proteins that directly bind to and inhibit caspases. As such, cIAP2 can protect a cell from apoptosis by inhibiting the activity of caspases.
Methods: Inbred C57BL/6 mice of two genotypes were used; cIAP2 +/+ x Apo E −/− (WT, n = 13) and cIAP2 −/− x Apo E −/− (KO, n = 10). At 8 weeks (wk), male mice were put on a high-fat diet (HFD) for a period 4 wk and 12 wk. Following the HFD period, mice were sacrificed by pentobarbital overdose, and tissues were harvested. The aortic root was serially sectioned into 90 sections, 10 μm apart. Sections were stained with SUDAN IV and lipid uptake was quantified. The arch and descending aorta were examined by en face methods and lesion surface area was quantified as % of total surface. Blood was processed for Fast Protein Liquid Chromatography (FPLC) and total cholesterol content.
Results: Ex vivo results of mice on a 4wk HFD show a significant decrease in lesion area at the aortic arch KO mice vs. WT; 0.53% ± 0.26 vs. 1.65% ± 0.86 (P, 0.05). Furthermore, aortic root lesion analysis show a similar trend with a decrease in lesions size in KO vs WT; 0.0217 ± 0.014 vs.0.0864 mm2 ± 0.1050. Ex vivo results of mice on a 12 wk HFD show a significant decrease in lesion area at the aortic arch KO mice vs. WT; 8.63% ± 3.63 vs. 17.22% ± 6.22 (p = <0.001).
Results also show a decrease in aortic root lesion size in KO vs. WT; 0.2692 mm2 ± 0.0941 vs. 0.4467 mm2 ± 0.1242 (p = <0.05). Total cholesterol assays and serum FPLC profiles between the groups showed no significant differences.
Conclusions: cIAP2 KO mice resulted in significantly reduced lesion development when compared to WT mice. These studies demonstrate the importance of cIAP2 as a survival factor for lesion associated macrophages, since loss of cIAP2 expression by macrophages helped protect mice from developing atherosclerotic lesions. These results indicate a prominent role for cIAP2 in atherosclerotic lesion formation and suggest that cIAP2 may provide a novel target for therapy.
- © 2010 by American Heart Association, Inc.