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2015 ; 290
(42
): 25475-86
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Ganglioside GM1 Contributes to the State of Insulin Resistance in Senescent Human
Arterial Endothelial Cells
#MMPMID26338710
Sasaki N
; Itakura Y
; Toyoda M
J Biol Chem
2015[Oct]; 290
(42
): 25475-86
PMID26338710
show ga
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.
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