論文 - 詳細
| RRC ID | 6058 |
|---|---|
| 著者 | Zakkar M, Van der Heiden K, Luong le A, Chaudhury H, Cuhlmann S, Hamdulay SS, Krams R, Edirisinghe I, Rahman I, Carlsen H, Haskard DO, Mason JC, Evans PC. |
| タイトル | Activation of Nrf2 in endothelial cells protects arteries from exhibiting a proinflammatory state. |
| ジャーナル | Arterioscler Thromb Vasc Biol |
| Abstract |
OBJECTIVE:Proinflammatory mediators influence atherosclerosis by inducing adhesion molecules (eg, VCAM-1) on endothelial cells (ECs) via signaling intermediaries including p38 MAP kinase. Regions of arteries exposed to high shear stress are protected from inflammation and atherosclerosis, whereas low-shear regions are susceptible. Here we investigated whether the transcription factor Nrf2 regulates EC activation in arteries. METHODS AND RESULTS:En face staining revealed that Nrf2 was activated in ECs at an atheroprotected region of the murine aorta where it negatively regulated p38-VCAM-1 signaling, but was expressed in an inactive form in ECs at an atherosusceptible site. Treatment with sulforaphane, a dietary antioxidant, activated Nrf2 and suppressed p38-VCAM-1 signaling at the susceptible site in wild-type but not Nrf2(-/-) animals, indicating that it suppresses EC activation via Nrf2. Studies of cultured ECs revealed that Nrf2 inactivates p38 by suppressing an upstream activator MKK3/6 and by enhancing the activity of the negative regulator MKP-1. CONCLUSIONS:Nrf2 prevents ECs at the atheroprotected site from exhibiting a proinflammatory state via the suppression of p38-VCAM-1 signaling. Pharmacological activation of Nrf2 reduces EC activation at atherosusceptible sites and may provide a novel therapeutic strategy to prevent or reduce atherosclerosis. |
| 巻・号 | 29(11) |
| ページ | 1851-7 |
| 公開日 | 2009-11-1 |
| DOI | 10.1161/ATVBAHA.109.193375 |
| PII | ATVBAHA.109.193375 |
| PMID | 19729611 |
| MeSH | Animals Arteries / enzymology* Arteries / physiopathology Arteritis / metabolism Arteritis / prevention & control* Cells, Cultured / cytology Cells, Cultured / metabolism Disease Models, Animal Endothelial Cells / cytology Endothelial Cells / drug effects Enzyme Activation Inflammation Mediators / metabolism Isothiocyanates Male Mice Mice, Inbred C57BL NF-E2-Related Factor 2 / drug effects NF-E2-Related Factor 2 / metabolism* Phosphorylation / physiology Random Allocation Sensitivity and Specificity Shear Strength Signal Transduction Sulfoxides Thiocyanates / pharmacology* p38 Mitogen-Activated Protein Kinases / drug effects p38 Mitogen-Activated Protein Kinases / genetics p38 Mitogen-Activated Protein Kinases / metabolism* |
| IF | 6.604 |
| 引用数 | 160 |
| WOS 分野 | PERIPHERAL VASCULAR DISEASE HEMATOLOGY |
| リソース情報 | |
| 実験動物マウス | RBRC01390 |