Relative Reduction of Endothelial Nitric-Oxide Synthase Expression and Transcription in Atherosclerosis-Prone Regions of the Mouse Aorta and in an in Vitro Model of Disturbed Flow
| Autor: | Anouk-Martine Teichert, Charles C. Matouk, Jason E. Fish, Su-Ning Zhu, Michael Bonert, Myron I. Cybulsky, Mian Chen, Matadial Ojha, Philip A. Marsden, Doyon Won |
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| Rok vydání: | 2007 |
| Předmět: |
Genetically modified mouse
Brachial Artery Nitric Oxide Synthase Type III Transcription Genetic Endothelium Swine Nitric Oxide Synthase Type II Mice Transgenic RNA polymerase II 030204 cardiovascular system & hematology Pathology and Forensic Medicine Mice 03 medical and health sciences 0302 clinical medicine Transcription (biology) Enos Gene expression medicine Animals RNA Messenger Phosphorylation Aorta 030304 developmental biology 0303 health sciences Reporter gene biology Transcription Factor RelA Atherosclerosis biology.organism_classification Cell biology Mice Inbred C57BL Endothelial stem cell medicine.anatomical_structure Regional Blood Flow Immunology biology.protein Endothelium Vascular Shear Strength Regular Articles |
| Zdroj: | The American Journal of Pathology. 171:1691-1704 |
| ISSN: | 0002-9440 |
| DOI: | 10.2353/ajpath.2007.060860 |
| Popis: | Atherosclerosis develops in distinct regions of the arterial tree. Defining patterns and mechanisms of endothelial cell gene expression in different regions of normal arteries is key to understanding the initial molecular events in atherogenesis. In this study, we demonstrated that the expression of endothelial nitric-oxide synthase (eNOS), an atheroprotective gene, and its phosphorylation on Ser(1177), a marker of activity, were lower in regions of the normal mouse aorta that are predisposed to atherosclerosis. The same expression pattern was observed in mouse strains that are both susceptible and resistant to atherosclerosis, and the topography of eNOS expression was inverse to p65, the main nuclear factor-kappaB subunit. Modeling of disturbed and uniform laminar flow in vitro reproduced the expression patterns of eNOS and p65 that were found in vivo. Heterogeneous nuclear RNA expression and RNA polymerase II chromosome immunoprecipitation studies demonstrated that regulation of transcription contributed to increased eNOS expression in response to shear stress. In vivo, the transcription of eNOS was reduced in regions of the mouse aorta predisposed to atherosclerosis, as defined by reporter gene expression in eNOS promoter-beta-galactosidase reporter transgenic mice. These data suggest that disturbed hemodynamic patterns found at arterial branches and curvatures uniquely modulate endothelial cell gene expression by regulating transcription, potentially explaining why these regions preferentially develop atherosclerosis when risk factors such as hypercholesterolemia are introduced. |
| Databáze: | OpenAIRE |
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