| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Naganuma, Eriko Moriguchi, Takashi Yamamoto, Masayuki Keleku-lukwete, Nadine Tanabe, Osamu Otsuki, Akihito Hayashi, Makiko Engel, James Douglas Suzuki, Mikiko Katayama, Saori Tsuchida, Kouhei Imaizumi, Masue |
| Description |
Author Affiliation: Keleku-Lukwete N ( Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan); Suzuki M ( Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan); Otsuki A ( Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan); Tsuchida K ( Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan); Katayama S ( Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan); Hayashi M ( Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan); Naganuma E ( Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan); Moriguchi T ( Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan); Tanabe O ( Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan); Engel JD ( Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109.); Imaizumi M ( Department of Hematology and Oncology, Miyagi Children's Hospital, Sendai 989-3126, Japan); Yamamoto M ( Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan); |
| Abstract |
Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the ß-globin gene, leading to the production of abnormally shaped red blood cells. Sickle cells are prone to hemolysis and thereby release free heme into plasma, causing oxidative stress and inflammation that in turn result in damage to multiple organs. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of the antioxidant cell-defense system. Here we show that constitutive Nrf2 activation by ablation of its negative regulator Keap1 (kelch-like ECH-associated protein 1) significantly improves symptoms in SCD model mice. SCD mice exhibit severe liver damage and lung inflammation associated with high expression levels of proinflammatory cytokines and adhesion molecules compared with normal mice. Importantly, these symptoms subsided after Nrf2 activation. Although hemolysis and stress erythropoiesis did not change substantially in the Nrf2-activated SCD mice, Nrf2 promoted the elimination of plasma heme released by sickle cells' hemolysis and thereby reduced oxidative stress and inflammation, demonstrating that Nrf2 activation reduces organ damage and segregates inflammation from prevention of hemolysis in SCD mice. Furthermore, administration of the Nrf2 inducer CDDO-Im (2-cyano-3, 12 dioxooleana-1, 9 diene-28-imidazolide) also relieved inflammation and organ failure in SCD mice. These results support the contention that Nrf2 induction may be an important means to protect organs from the pathophysiology of sickle cell-induced damage. |
| ISSN |
00278424 |
| e-ISSN |
10916490 |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number |
39 |
| Volume Number |
112 |
| Language |
English |
| Publisher |
National Academy of Sciences |
| Publisher Date |
2015-09-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Anemia, Sickle Cell Complications Inflammation Genetics Therapy Liver Pathology NF-E2-Related Factor 2 Metabolism Oxidative Stress Transcriptional Activation Adaptor Proteins, Signal Transducing Animals Cytoskeletal Proteins DNA Primers Flow Cytometry Gene Knockout Techniques Immunoblotting Luciferases Mice Real-Time Polymerase Chain Reaction Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Multidisciplinary |
