P1941The nuclear receptor corepressor 1 blocks CD36-mediated foam cell formation in atherogenesis

Abstract

Abstract Background Nuclear receptors and their cofactors regulate the expression of various target genes in different tissue and organs to orchestrate downstream (patho)physiological processes. Although the function of several nuclear receptors in atherosclerosis has been studied, very little is known about the role of nuclear receptor cofactors in atherosclerosis. Given its important role to suppress inflammatory processes, we speculated that macrophage nuclear receptor corepressor 1 (NCOR1) plays a protective function in atherosclerosis development. Purpose To evaluate the contribution of macrophage NCOR1 in atherosclerosis we used myeloid cell-specific Ncor1 knockout mice on an atherosclerosis-prone background. Methods and results 8-week-old male and female mice were exposed to a high high-cholesterol diet for 12 weeks. Our findings demonstrate that the lack of macrophage Ncor1 leads to a severe atherosclerotic phenotype in both sexes. These mice show a higher content of plaques along the thoraco-abdominal aortae as well as at the aortic sinus, which were characterized by larger necrotic cores and thinner fibrous caps, a typical signature of unstable plaques. Moreover, we found that the pro-atherogenic effects of the Ncor1 deletion are mediated via derepression of peroxisome proliferator-activated receptor gamma (PPARγ) target genes in mouse and human macrophages, especially the enhanced expression of the CD36 scavenger receptor and the subsequent rise in oxLDL uptake. Interestingly, while the expression of NCOR1 is reduced, the PPARγ signature is increased in human atherosclerotic plaques, and this signature is further pronounced in ruptured compared to stable carotid plaques. Conclusion Our findings suggest that macrophage NCOR1 blocks the pro-atherogenic functions of PPARγ in atherosclerosis and prevents the disease development. Acknowledgement/Funding The Swiss National Science Foundation, the Novartis Foundation, Olga-Mayenfisch Foundation, the OPO foundation