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, α‐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.