Journal of Biological Chemistry
Volume 290, Issue 42, 16 October 2015, Pages 25475-25486
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Cell Biology
Ganglioside GM1 Contributes to the State of Insulin Resistance in Senescent Human Arterial Endothelial Cells*

https://doi.org/10.1074/jbc.M115.684274Get rights and content
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Vascular endothelial cells (ECs) play central roles in physiologically important functions of blood vessels and contribute to the maintenance of vascular integrity. Therefore, it is considered that the impairment of EC functions leads to the development of vascular diseases. However, the molecular mechanisms of the EC dysfunctions that accompany senescence and aging have not yet been clarified. The carbohydrate antigens carried by glycoconjugates (e.g. glycoproteins, glycosphingolipids, and proteoglycans) mainly present on the cell surface serve not only as marker molecules but also as functional molecules. In this study, we have investigated the abundance and functional roles of glycosphingolipids in human ECs during senescence and aging. Among glycosphingolipids, ganglioside GM1 was highly expressed in abundance on the surface of replicatively and prematurely senescent ECs and also of ECs derived from an elderly subject. Insulin signaling, which regulates important functions of ECs, is impaired in senescent and aged ECs. Actually, by down-regulating GM1 on senescent ECs and overloading exogenous GM1 onto non-senescent ECs, we showed that an increased abundance of GM1 functionally contributes to the impairment of insulin signaling in ECs. Taken together, these findings provide the first evidence that GM1 increases in abundance on the cell surface of ECs under the conditions of cellular senescence and aging and causes insulin resistance in ECs. GM1 may be an attractive target for the detection, prevention, and therapy of insulin resistance and related vascular diseases, particularly in older people.

aging
endothelial cell
endothelial dysfunction
ganglioside
insulin resistance
senescence
GM1

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*

This work was supported by Japan Society for the Promotion of Science KAKENHI Grant 24890298, grant-in-aid for young scientists (start-up), grant-in-aid for scientific research (C), and grant-in-aid for challenging exploratory research, and Terumo Life Science Foundation (2013 general subsidy). The authors declare that they have no conflicts of interest with the contents of this article.