title: Endothelial cellular senescence is inhibited by liver X receptor activation with an additional mechanism for its atheroprotection in diabetes.
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) β-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 LXRβ mediates the prevention of endothelial cellular senescence, and that sterol regulatory element binding protein-1, which was up-regulated as a direct LXRβ 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 β-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.
authors.affiliation: Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Hayashi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kotani
authors.forename: Tomoe
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Kumiko
authors.initials: K
authors.lastname: Taguchi
authors.forename: Mayu
authors.initials: M
authors.lastname: Iida
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ina
authors.forename: Morihiko
authors.initials: M
authors.lastname: Maeda
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kuzuya
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hattori
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ignarro
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000150:complications / Q000517:prevention & control*; D016922:Cellular Senescence; D003720:Densitometry; D048909:Diabetes Complications / Q000517:prevention & control*; D003920:Diabetes Mellitus / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000628:therapy; D004730:Endothelium, Vascular / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation; D008024:Ligands; D000071518:Liver X Receptors; D008156:Luciferases / Q000378:metabolism; D008687:Metformin / Q000737:chemistry; D018613:Microscopy, Confocal; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000648:ultrastructure
chemical_list: D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D017382:Reactive Oxygen Species; D008687:Metformin; D008156:Luciferases; D019098:Telomerase
keywords: T0901317; cholesterol efflux transporter