Loss of Cellular Inhibitor of Apoptosis Protein 2 Reduces Atherosclerosis in Atherogenic apoE-/- C57BL/6 Mice on High-Fat Diet

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, alpha-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 mm(2) versus cIAP2(+/+) 0.0515 +/- 0.021 mm(2) [P=0.022]); (cIAP2(-/-) 0.3614 +/- 0.1157 mm(2) versus cIAP2(+/+) 0.4901 +/- 0.125 mm(2) [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.