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.T0901317 | cholesterol efflux transporter N uclear receptors are ligand-activated transcription factors that play an important role in the regulation of cellular metabolic function such as lipid and glucose metabolism (1). Dysregulation of these processes causes development of metabolic diseases such as hyperlipidemia, diabetes, and cardiovascular disease. In humans, 48 different types of nuclear receptors have been identified. These include the receptor for a metabolite of vitamin A, retinoic acid, retinoic acid receptor (RAR); the vitamin D receptor (VDR); the fatty acid receptor, peroxisome proliferator-activated receptor γ (PPARγ); the oxysterol receptor, liver X receptor (LXR); and their obligate heterodimeric partner, the retinoid X receptor (RXR) (2, 3). LXRs act as potent transcriptional switches for the coordinated regulation of genes involved in the control of hepatic lipid and cholesterol metabolism, and have a crucial role in reverse cholesterol transport,

Activation of liver X receptor attenuates lysophosphatidylcholine‐induced IL‐8 expression in endothelial cells via the NF‐κB pathway and SUMOylation

“…showed that the activation of LXR inhibits endothelial cell senescence. Therefore, it improves endothelial dysfunction and suppresses the progression of atherosclerosis . Treatment of LXRα −/− apoE −/− mice with a synthetic LXR ligand ameliorates the cholesterol overload phenotype and reduced atherosclerosis, suggesting that LXRβ plays an important role in this procedure .…”

“…Liver X receptor β represents the most important LXR isoform in endothelial cells. Activating of LXRβ prevents endothelial cellular senescence by up‐regulating the target gene sterol regulatory element binding protein‐1 . Besides, LXRβ activation reduces overproduction of reactive oxygen species and increases endothelial nitric oxide synthase activity, which stimulates the migration of endothelial cells and preserves endothelial integrity .…”

Krüppel-Like Factor 4 Regulation of Cholesterol-25-Hydroxylase and Liver X Receptor Mitigates Atherosclerosis Susceptibility

“…Belonging to the nuclear receptor superfamily, LXR transactivates genes such as ATP-binding cassette (ABC) transporters, ABCA1 and ABCG1, to promote reverse cholesterol transport (RCT) 16 . Ligand-dependent LXR activation in ECs is associated with reduced oxidative stress and increased eNOS activity 17 . Furthermore, administration of a synthetic LXR ligand to ApoE −/− or LDLR −/− mice decreased atherosclerosis 18 .…”

Loss of the Liver X Receptors Disrupts the Balance of Hematopoietic Populations, With Detrimental Effects on Endothelial Progenitor Cells

“…7 A role for LXRs in endothelial cell homeostasis has been previously described in which LXRs were beneficial in preventing endothelial cell activation and senescence, as well as in promoting overall endothelial health. [8][9][10] However, preservation of the endothelium is not solely mediated by direct effects on endothelial cells. Bone marrow (BM)-derived endothelial progenitor cells (EPCs) are also responsible for promoting endothelial cell maintenance.…”