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 (c IAP 2) 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 c IAP 2 on atherosclerosis lesion development. Methods and Results We used apoE −/− C57BL/6 male mice, either c IAP 2 −/− or c IAP 2 +/+ . 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, CD 68, α‐actin, and terminal deoxynucleotidyl transferase dUTP nick end labeling ( TUNEL ). c IAP 2 −/− 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 ( c IAP 2 −/− 0.58±0.37% versus c IAP 2 +/+ 1.51±0.79% [ P =0.0056]); ( c IAP 2 −/− 9.34±4.88% versus c IAP 2 +/+ 17.65±6.24% [ P =0.0019]). Aortic root lesion area after 4 and 12 weeks of HFD also decreased ( c IAP 2 −/− 0.0328±0.014 mm 2 versus c IAP 2 +/+ 0.0515±0.021 mm 2 [ P =0.022]); ( c IAP 2 −/− 0.3614±0.1157 mm 2 versus c IAP 2 +/+ 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 ( c IAP 2 −/− 4.47±2.26% versus c IAP 2 +/+ 1.74±0.98% [ P =0.036]); ( c IAP 2 −/− 2.39±0.75% versus c IAP 2 +/+ 1.29±0.47% [ P =0.032]). Smooth muscle cell content in c IAP 2 −/− mice was 3.075±3.3% compared with c IAP 2 +/+ with 0.085±0.1% ( P =0.0071). Conclusions Results uncover a key role for c IAP 2 in atherosclerotic lesion development, and targeting it may represent a novel therapeutic strategy.