Oncotarget

Research Papers: Gerotarget (Focus on Aging):

Ganglioside GM1 contributes to extracellular/intracellular regulation of insulin resistance, impairment of insulin signaling and down-stream eNOS activation, in human aortic endothelial cells after short- or long-term exposure to TNFα

Norihiko Sasaki, Yoko Itakura and Masashi Toyoda _

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Oncotarget. 2018; 9:5562-5577. https://doi.org/10.18632/oncotarget.23726

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Abstract

Norihiko Sasaki1, Yoko Itakura1 and Masashi Toyoda1

1Research Team for Geriatric Medicine, Vascular Medicine, Tokyo Metropolitan Institute of Gerontology, Sakaecho 35-2, Itabashi-Ku, Tokyo 173-0015, Japan

Correspondence to:

Masashi Toyoda, email: mtoyoda@tmig.or.jp

Keywords: TNFα; vascular insulin resistance; GM1; aortic endothelial cell; aging

Received: June 21, 2017     Accepted: October 15, 2017     Published: December 15, 2017

ABSTRACT

Vascular insulin resistance induced by inflammatory cytokines leads to the initiation and development of vascular diseases. In humans, circulating TNFα levels are increased during aging, suggesting a correlation between vascular insulin resistance and plasma TNFα levels. Currently, the precise molecular mechanisms of vascular insulin resistance mediated by TNFα are not well characterized. We aimed at clarifying whether glycosphingolipids contribute to vascular insulin resistance after inflammatory stimulation. In this study, we examined vascular insulin resistance using human aortic endothelial cells after treatment with different concentrations of TNFα for different time intervals for mimicking in vivo acute or chronic inflammatory situations. We show that ganglioside GM1 levels on cell membranes change depending on time of exposure to TNFα and its concentration and that the GM1 expression is associated with specific extracellular/intracellular regulation of the insulin signaling cascade. Furthermore, we provide evidence that factors such as aging and senescence affect the regulation of insulin resistance. Our data suggest that GM1 is a key player in the induction of vascular insulin resistance after short- or long-term exposure to TNFα and is a good extracellular target for prevention and cure of vascular diseases.


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