Sara Oppi1, Stefanie Nusser-Stein1, Przemyslaw Blyszczuk2,3, Xu Wang4, Anne Jomard5,6, Vincenzo Marzolla1,7, Kangmin Yang1, Srividya Velagapudi1, Liam J Ward8, Xi-Ming Yuan8, Martin A Geiger9, Ana T Guillaumon9, Alaa Othman6, Thorsten Hornemann6, Zoran Rancic10, Dongryeol Ryu11, Maaike H Oosterveer12, Elena Osto1,5,6, Thomas F Lüscher1,13,14, Sokrates Stein1. 1. Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland. 2. Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, 8091 Zurich, Switzerland. 3. Department of Clinical Immunology, Jagiellonian University Medical College, 31-008 Cracow, Poland. 4. Department of Plant Science, School of Agriculture and Biology, Shanghai Jiao Tong University, 200240 Shanghai, China. 5. Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, ETH Zurich, 8603 Schwerzenbach, Switzerland. 6. Institute for Clinical Chemistry, University Hospital Zurich, 8091 Zurich, Switzerland. 7. Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, 00163 Rome, Italy. 8. Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden. 9. Vascular Diseases Discipline, Clinics Hospital of the University of Campinas, 13083-970 Campinas, Brazil. 10. Clinic for Vascular Surgery, University Hospital Zurich, 8091 Zurich, Switzerland. 11. Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 16419 Suwon, Republic of Korea. 12. Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, 9713 Groningen, The Netherlands. 13. Department of Cardiology, Royal Brompton & Harefield Hospital Trust, London, SW3 6NP, UK. 14. Imperial College London, London, SW7 2AZ, UK.
Abstract
AIMS: Nuclear receptors and their cofactors regulate key pathophysiological processes in atherosclerosis development. The transcriptional activity of these nuclear receptors is controlled by the nuclear receptor corepressors (NCOR), scaffolding proteins that form the basis of large corepressor complexes. Studies with primary macrophages demonstrated that the deletion of Ncor1 increases the expression of atherosclerotic molecules. However, the role of nuclear receptor corepressors in atherogenesis is unknown. METHODS AND RESULTS: We generated myeloid cell-specific Ncor1 knockout mice and crossbred them with low-density lipoprotein receptor (Ldlr) knockouts to study the role of macrophage NCOR1 in atherosclerosis. We demonstrate that myeloid cell-specific deletion of nuclear receptor corepressor 1 (NCOR1) aggravates atherosclerosis development in mice. Macrophage Ncor1-deficiency leads to increased foam cell formation, enhanced expression of pro-inflammatory cytokines, and atherosclerotic lesions characterized by larger necrotic cores and thinner fibrous caps. The immunometabolic effects of NCOR1 are mediated via suppression of peroxisome proliferator-activated receptor gamma (PPARγ) target genes in mouse and human macrophages, which lead to an enhanced expression of the CD36 scavenger receptor and subsequent increase in oxidized low-density lipoprotein uptake in the absence of NCOR1. Interestingly, in human atherosclerotic plaques, the expression of NCOR1 is reduced whereas the PPARγ signature is increased, and this signature is more pronounced in ruptured compared with non-ruptured carotid plaques. CONCLUSIONS: Our findings show that macrophage NCOR1 blocks the pro-atherogenic functions of PPARγ in atherosclerosis and suggest that stabilizing the NCOR1-PPARγ binding could be a promising strategy to block the pro-atherogenic functions of plaque macrophages and lesion progression in atherosclerotic patients. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Nuclear receptors and their cofactors regulate key pathophysiological processes in atherosclerosis development. The transcriptional activity of these nuclear receptors is controlled by the nuclear receptor corepressors (NCOR), scaffolding proteins that form the basis of large corepressor complexes. Studies with primary macrophages demonstrated that the deletion of Ncor1 increases the expression of atherosclerotic molecules. However, the role of nuclear receptor corepressors in atherogenesis is unknown. METHODS AND RESULTS: We generated myeloid cell-specific Ncor1 knockout mice and crossbred them with low-density lipoprotein receptor (Ldlr) knockouts to study the role of macrophage NCOR1 in atherosclerosis. We demonstrate that myeloid cell-specific deletion of nuclear receptor corepressor 1 (NCOR1) aggravates atherosclerosis development in mice. Macrophage Ncor1-deficiency leads to increased foam cell formation, enhanced expression of pro-inflammatory cytokines, and atherosclerotic lesions characterized by larger necrotic cores and thinner fibrous caps. The immunometabolic effects of NCOR1 are mediated via suppression of peroxisome proliferator-activated receptor gamma (PPARγ) target genes in mouse and human macrophages, which lead to an enhanced expression of the CD36 scavenger receptor and subsequent increase in oxidized low-density lipoprotein uptake in the absence of NCOR1. Interestingly, in human atherosclerotic plaques, the expression of NCOR1 is reduced whereas the PPARγ signature is increased, and this signature is more pronounced in ruptured compared with non-ruptured carotid plaques. CONCLUSIONS: Our findings show that macrophage NCOR1 blocks the pro-atherogenic functions of PPARγ in atherosclerosis and suggest that stabilizing the NCOR1-PPARγ binding could be a promising strategy to block the pro-atherogenic functions of plaque macrophages and lesion progression in atherosclerotic patients. Published on behalf of the European Society of Cardiology. All rights reserved.
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