J Biol Chem. 2015 Oct 16;290(42):25475-86.
Ganglioside GM1 Contributes to the State of Insulin Resistance in Senescent Human Arterial Endothelial Cells.
- 1From the Research Team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Sakaecho 35-2, Itabashi-ku, Tokyo 173-0015, Japan.
- 2From the Research Team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Sakaecho 35-2, Itabashi-ku, Tokyo 173-0015, Japan firstname.lastname@example.org.
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.
KEYWORDS: GM1; aging; endothelial cell; endothelial dysfunction; ganglioside; insulin resistance; senescence
Insulin signaling regulates important functions in ECs and contributes to the maintenance of vascular integrity. For example, insulin signaling in ECs modulates NO production by endothelial NO synthase (eNOS) activation and the expression of adhesion molecules, and it also attenuates the progression of atherosclerosis (1-3). Recently, it has been demonstrated that insulin resistance in ECs cause skeletal muscle insulin resistance as a consequence of the impaired insulin-induced capillary recruitment and insulin delivery, resulting in initiation of diabetes (4). So, insulin resistance in ECs is considered to lead to the initiation and progression of diabetes and vascular diseases (3, 4). Furthermore, about insulin resistance in others such as adipocyte and muscle, many reports have demonstrated the molecular mechanisms and inflammatory effect (5-7). However, currently, there are unsolved issues particularly in the context of aging and senescence that which is the trigger of insulin resistance and how is the interaction of organs in insulin resistance? In this study, we have demonstrated that the abundance of ganglioside GM1 increases on the cell surface of senescent and aged ECs and contributes to insulin resistance in senescent ECs. Thus, there is possibility that our present report is a cue to elucidate the unsolved issues.
It has been well known that the amount and composition of gangliosides in the cell membrane can change dependent on the cellular condition, such as developmental and pathological state (8). Furthermore, gangliosides are fine regulators of receptor tyrosine kinases signaling, including insulin signaling, and that changed cell surface gangliosides compositions in physio-pathological conditions result in altered cellular responses (9, 10). In 3T3-L1 adipocytes, the monosialodihexosylganglioside (GM3) was found to contribute to insulin resistance in pathological conditions such as obesity (11, 12). In this study, we have demonstrated that an increased abundance of GM1 produces insulin resistance in ECs. We also investigated the abundances of gangliosides in ECs after TNFα (one of obesity-linked factors) treatment. In ECs, GM1 was increased but GM3 was not (unpublished data). Furthermore, in transgenic mice showing insulin resistance, NEU3 overexpression induced increases in the abundances of GM1 and GM2 mainly in muscles (13). On the other hand, reduction of GM3 in the livers via hepatic NEU3 overexpression improved insulin sensitivity and glucose tolerance in mice, indicating that GM3 contributes to insulin resistance in liver (14). Thus, it is possible that the abundances of gangliosides related to insulin resistance differ among cell types and tissues (Figure 1). It was shown that potent inhibitors of GSLs improve ganglioside-mediated insulin sensitivity in pathological model mice (15-17). So, it is considered that gangliosides really play important roles in insulin resistance and –related diseases. However, the remaining issues are that which ganglioside is key contributor to initiation of insulin resistance-related diseases in older people. Therefore, clarifying the significance of the abundance of each ganglioside in relation to tissue-specific insulin resistance could lead to a deeper understanding of each pathological condition and thus to more efficient drug discovery for the treatment of insulin resistance-related diseases in older people.
Figure. 1 Insulin resistance-related gangliosides are different dependent on each tissues and cells.
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