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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Iida, Mayu Hattori, Yuichi Kuzuya, Masafumi Maeda, Morihiko Taguchi, Kumiko Yamaguchi, Tomoe Ignarro, Louis J. Hayashi, Toshio Kotani, Hitoshi Ina, Koichiro |
| Description | Author Affiliation: Hayashi T ( Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.); |
| Abstract | Senescence of vascular endothelial cells leads to endothelial dysfunction and contributes to the progression of atherosclerosis. Liver X receptors (LXRs) are nuclear receptors whose activation protects against atherosclerosis by transcriptional regulation of genes important in promoting cholesterol efflux and inhibiting inflammation. Here we found that LXR activation with specific ligands reduced the increase in senescence-associated (SA) ß-gal activity, a senescence marker, and reversed the decrease in telomerase activity, a replicative senescence marker, in human endothelial cells under high glucose. This effect of LXR activation was associated with reduced reactive oxygen species and increased endothelial NO synthase activity. A series of experiments that used siRNAs indicated that LXRß mediates the prevention of endothelial cellular senescence, and that sterol regulatory element binding protein-1, which was up-regulated as a direct LXRß target gene, may act as a brake of endothelial cellular senescence. Although oral administration of the LXR ligand led to severe fatty liver in diabetic rats, concomitant therapy with metformin avoided the development of hepatic steatosis. However, the preventive effect of the LXR ligand on SA ß-gal-stained cells in diabetic aortic endothelium was preserved even if metformin was coadministered. Taken together, our studies demonstrate that an additional mechanism, such as the regulation of endothelial cellular senescence, is related to the antiatherogenic properties of LXRs, and concomitant treatment with metformin may provide a clinically useful therapeutic strategy to alleviate an LXR activation-mediated adverse effects on liver triglyceride metabolism. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 3 |
| Volume Number | 111 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2014-01-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Atherosclerosis Prevention & Control Cell Aging Diabetes Complications Endothelium, Vascular Metabolism Orphan Nuclear Receptors Administration, Oral Animals Aorta Pathology Complications Densitometry Diabetes Mellitus Diabetes Mellitus, Experimental Therapy Human Umbilical Vein Endothelial Cells Inflammation Ligands Luciferases Metformin Chemistry Microscopy, Confocal Rats, Sprague-Dawley Reactive Oxygen Species Telomerase Telomere Ultrastructure Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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