Loss of cellular inhibitor of apoptosis protein 2 reduces atherosclerosis in atherogenic apoe-/- C57BL/6 mice on high-fat diet

Abstract

Background--Cellular inhibitor of apoptosis protein 2 (cIAP2) is predicted to participate in atherosclerosis; however, its direct role in atherosclerosis development has not been investigated. We aimed to examine and assess the loss of cIAP2 on atherosclerosis lesion development. Methods and Results--We used apoE-/- C57BL/6 male mice, either cIAP2-/- or cIAP2+/+. At 8 weeks, mice were fed a high-fat diet (HFD) for 4 and 12 weeks. Aortic root was serially sectioned and stained with Sudan IV, CD68, a-actin, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). cIAP2-/- mice displayed a significant decrease in atherosclerotic lesion's macrophage number after 4 weeks of HFD. Similarly, decrease in lesion area at 4 and 12 weeks HFD was detected by use of en face analysis (cIAP2-/- 0.58±0.37% versus cIAP2+/+ 1.51±0.79% [P=0.0056]); (cIAP2-/- 9.34±4.88% versus cIAP2+/+ 17.65±6.24% [P=0.0019]). Aortic root lesion area after 4 and 12 weeks of HFD also decreased (cIAP2-/- 0.0328±0.014 mm2 versus cIAP2+/+ 0.0515±0.021 mm2 [P=0.022]); (cIAP2-/- 0.3614±0.1157 mm2 versus cIAP2+/+ 0.4901±0.125 mm2 [P=0.065]). TUNEL analysis after 4 and 12 weeks of HFD showed a 2.5-fold increase in TUNEL+ cells (cIAP2-/- 4.47±2.26% versus cIAP2+/+ 1.74±0.98% [P=0.036]); (cIAP2-/- 2.39±0.75% versus cIAP2+/+ 1.29±0.47% [P=0.032]). Smooth muscle cell content in cIAP2-/- mice was 3.075±3.3% compared with cIAP2+/+ with 0.085±0.1% (P=0.0071). Conclusions--Results uncover a key role for cIAP2 in atherosclerotic lesion development, and targeting it may represent a novel therapeutic strategy.