Tao Zhuang1, Jie Liu1, Xiaoli Chen1, Lin Zhang1, Jingjiang Pi2, Huimin Sun1, Li Li3, Robert Bauer4, Haikun Wang5, Zuoren Yu1, Qi Zhang2, Brian Tomlinson6, Paul Chan7, Xiangjian Zheng8,9, Edward Morrisey10,11,12,13, Zhongmin Liu1, Muredach Reilly14, Yuzhen Zhang1. 1. From the Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine (T.Z., J.L., X.C., L.Z., H.S., Z.Y., Z.L., Y.Z.), Shanghai East Hospital, Tongji University School of Medicine, China. 2. Cardiology (J.P., Q.Z.), Shanghai East Hospital, Tongji University School of Medicine, China. 3. Cardiovascular Institute, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (L.L.). 4. Cardiology Division, Department of Medicine (R.B.), Columbia University, New York, NY. 5. Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (H.W.). 6. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR (B.T.). 7. Division of Cardiology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taiwan (P.C.). 8. Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University (X.Z.). 9. Laboratory of Cardiovascular Signaling, Centenary Institute, and Sydney Medical School, University of Sydney, Sydney, NSW, Australia (X.Z.). 10. Department of Cell and Developmental Biology (E.M.), University of Pennsylvania, Philadelphia. 11. Department of Medicine (E.M.), University of Pennsylvania, Philadelphia. 12. Penn Cardiovascular Institute (E.M.), University of Pennsylvania, Philadelphia. 13. Penn Institute for Regenerative Medicine (E.M.), University of Pennsylvania, Philadelphia. 14. Cardiology Division, Department of Medicine and the Irving Institute for Clinical and Translational Research (M.R.), Columbia University, New York, NY.
Abstract
RATIONALE: Endothelial dysfunction results in sustained and chronic vascular inflammation, which is central to atherosclerotic diseases. However, transcriptional regulation of vascular endothelial inflammation has not been well clarified. OBJECTIVE: This study aims to explore Foxp (forkhead box P) transcription factor 1 in regulation of endothelial homeostasis, atherogenesis, and its mechanisms. METHODS AND RESULTS: To assess the importance of Foxp1 in atherosclerosis, Foxp1 expression was analyzed in human coronary artery and mouse artery, and we observed significant downregulation of Foxp1 in atherosclerotic and atherosusceptible endothelium. Endothelial-specific Foxp1 knockout mice (Foxp1ECKO) were bred onto ApoeKO mice to generate endothelial Foxp1-deletion hyperlipidemic model Foxp1ECKO;ApoeKO, which displayed significant increases in atherosclerotic lesion formation in aortas and aortic roots with enhanced monocyte adhesion, migration, and infiltration into the vascular wall and formation of inflammatory lipid-laden macrophages. In contrast, endothelial-specific Foxp1 overexpression mice Foxp1ECTg;ApoeKO exhibited reduced atherosclerotic lesion formation with less monocyte infiltration. Foxp1 was further identified as a gatekeeper of vessel inflammation by direct regulation of endothelial inflammasome components, including Nlrp3 (NLR [nucleotide-binding and leucine-rich repeat immune receptors] family pyrin domain containing 3), caspase-1, and IL (interleukin)-1β. Moreover, endothelial Foxp1 was found to be regulated by Klf2 (Kruppel-like factor 2). Oscillatory shear stress downregulated Foxp1 expression via repressing Klf2 expression in endothelium, and, therefore, promoted endothelial inflammasome activation, leading to atherosclerotic lesion formation. Simvastatin upregulated the reduced expression of Klf2 and Foxp1 in atherosusceptible vascular endothelium and alleviated vascular inflammation contributing to its inhibitory effect in atherosclerosis. CONCLUSIONS: These data are the first in vivo experimental validation of an atheroprotective role of endothelial Klf2 and Foxp1, which reveals a Klf2-Foxp1 transcriptional network in endothelial cells as a novel regulator of endothelial inflammasome activation for atherogenesis, therefore, provides opportunities for therapeutic intervention of atherosclerotic diseases and uncovers a novel atheroprotective mechanism for simvastatin.
RATIONALE: Endothelial dysfunction results in sustained and chronic vascular inflammation, which is central to atherosclerotic diseases. However, transcriptional regulation of vascular endothelial inflammation has not been well clarified. OBJECTIVE: This study aims to explore Foxp (forkhead box P) transcription factor 1 in regulation of endothelial homeostasis, atherogenesis, and its mechanisms. METHODS AND RESULTS: To assess the importance of Foxp1 in atherosclerosis, Foxp1 expression was analyzed in human coronary artery and mouse artery, and we observed significant downregulation of Foxp1 in atherosclerotic and atherosusceptible endothelium. Endothelial-specific Foxp1 knockout mice (Foxp1ECKO) were bred onto ApoeKO mice to generate endothelial Foxp1-deletion hyperlipidemic model Foxp1ECKO;ApoeKO, which displayed significant increases in atherosclerotic lesion formation in aortas and aortic roots with enhanced monocyte adhesion, migration, and infiltration into the vascular wall and formation of inflammatory lipid-laden macrophages. In contrast, endothelial-specific Foxp1 overexpression mice Foxp1ECTg;ApoeKO exhibited reduced atherosclerotic lesion formation with less monocyte infiltration. Foxp1 was further identified as a gatekeeper of vessel inflammation by direct regulation of endothelial inflammasome components, including Nlrp3 (NLR [nucleotide-binding and leucine-rich repeat immune receptors] family pyrin domain containing 3), caspase-1, and IL (interleukin)-1β. Moreover, endothelial Foxp1 was found to be regulated by Klf2 (Kruppel-like factor 2). Oscillatory shear stress downregulated Foxp1 expression via repressing Klf2 expression in endothelium, and, therefore, promoted endothelial inflammasome activation, leading to atherosclerotic lesion formation. Simvastatin upregulated the reduced expression of Klf2 and Foxp1 in atherosusceptible vascular endothelium and alleviated vascular inflammation contributing to its inhibitory effect in atherosclerosis. CONCLUSIONS: These data are the first in vivo experimental validation of an atheroprotective role of endothelial Klf2 and Foxp1, which reveals a Klf2-Foxp1 transcriptional network in endothelial cells as a novel regulator of endothelial inflammasome activation for atherogenesis, therefore, provides opportunities for therapeutic intervention of atherosclerotic diseases and uncovers a novel atheroprotective mechanism for simvastatin.
Authors: Martin Schlegel; Monika Sharma; Emily J Brown; Alexandra A C Newman; Yannick Cyr; Milessa Silva Afonso; Emma M Corr; Graeme J Koelwyn; Coen van Solingen; Jonathan Guzman; Rubab Farhat; Cyrus A Nikain; Lianne C Shanley; Daniel Peled; Ann Marie Schmidt; Edward A Fisher; Kathryn J Moore Journal: Circ Res Date: 2021-07-22 Impact factor: 23.213