1. Please check and comment entries here.
Table of Contents

    Others

    Gangliosides in Vascular

    Subjects: Pathology
    View times: 290
    Submitted by:

    Abstract

    Vascular diseases, such as myocardial infarction and cerebral infarction, are most commonly caused by atherosclerosis, one of the leading causes of death worldwide. Several types of cells, such as vascular (endothelial cell), vascular-associated (smooth muscle cell and fibroblast) and inflammatory cells, are involved in plaque formation, plaque rupture and thrombus formation, which result in atherosclerosis. Gangliosides, a group of glycosphingolipids, are expressed on the surface of vascular, vascular-associated and inflammatory cells, where they play functional roles. Here we introduce gangliosides expressed on those cells and their relevance to vascular diseases.

    1. Introduction

    Blood vessel-constituting cells (ECs, VSMCs, fibroblasts) can be involved in atherosclerosis, leading to vascular diseases. Gangliosides are expressed on these cells (see Table 1) and their relevance to vascular diseases is detailed below.

    Table 1. Functional roles of endogenous or exogenous gangliosides in vascular and vascular-associated cells.

    Cell Type

    Sources

    Types of Gangliosides

    Functional Roles

    References

    GM 7373 cells (ECs)

    Bovine

    GM1

    Coreceptor of bFGF

    [1]

    BAECs

    Bovine

    GM2, GM1

    Inhibition of proliferation

    [2]

     

     

    GM3

    Promotion of proliferation

    [2]

    HUVECs

    Human

    GD1a

    Enhancement of VEGF-induced signaling, proliferation and migration

    [3]

     

     

    GM3

    Inhibition of VEGF signaling, angiogenesis and adhesion molecules

    [4][5]

    HAECs

    Human

    GM1

    Association with aging and Inhibition of insulin signaling

    [6][7]

    VSMCs

    Human

    GD3

    Modulation of proliferation and apoptosis

    [8]

    VSMCs

    Mouse

    GD3

    Inhibition of PDGF-induced ERK pathway and proliferation

    [9]

     

     

    GD3

    Inhibition of TNFα-induced MMP9 expression

    [9]

    VSMCs

    Rat

    GM2, GM1

    Activation of ERK pathway and promotion of proliferation

    [10]

    Fibroblasts (dermal)

     

    Human

    GM3, GD1a

    Promotion of EGF or bFGF stimulated proliferation

    [11][12]

     

     

    GD3

    Activation of autophagic process

    [13]

    Fibroblasts (embryonic)

    Mouse

    GM3

    Attenuation of FBS stimulated MAPK pathway

    [14]

    Fibroblasts (heart)

    Rat

    GM1

    Protection from apoptosis caused from protein kinase C inhibition

    [15]

    Neutrophils

    Human

    GM1

    Association with maturation

    [16][17]

     

     

    GM1

    Decrease at early stage of apoptosis

    [18]

    HMC-1 (mast cell line)

    Human

    GM3, GM2, GM1, GD1a

    Association with maturation

    [19]

    Mast cells

    Mouse

    GM3

    Inhibition of IL-3 stimulated proliferation

    [20]

    RBL-2H3 (mast cell line)

    Rat

    GD1b

    Activation and induction of inflammatory cytokines

    [21]

    HL-60, U937 (monocyte)

    Human

    GM3

    Induction of cell differentiation

    [22]

    Raw264.7 (macrophage)

    Mouse

    GM1

    Induction of arginase-1 and MCP-1

    [23]

    T cells

    Human

    GM3, GM1

    Association with activation

    [24]

    CD8+ T cells

    Human

    GM1

    Increase with IL-2 stimulation

    [25]

    CD4+ T cells

    Human

    GM3, GM1

    Downregulation of CD4 expression

    [26]

    Platelets

    Human

    GD3

    Association with activation

    [27][28]

     

     

    GM3, GM1

    Induction of activation with Ca2+ mobilization and shape change

    [29]

     

     

    GD2

    Induction of apoptosis

    [30]

    3T3-L1 (adipocyte)

    Mouse

    GM3

    Inhibition of insulin signaling

    [31]

    2. ECs and Gangliosides

    To date, several gangliosides have been reported to be expressed on ECs. In bovine aortic endothelial cells (BAECs), GM3 and GM1 are endogenously expressed[32]. Endogenous cell surface GM1 functions as a coreceptor for basic fibroblast growth factor (bFGF) in transformed fetal bovine aortic endothelial GM 7373 cells [26]. Exogenous addition of GM1 or GM2 inhibits bFGF-induced proliferation of BAECs, whereas GM3 enhances bFGF-induced proliferation[33]. In human umbilical vein endothelial cells (HUVECs), exogenous addition of GD1a enhances vascular endothelial growth factor (VEGF)-induced signaling, involved in proliferation and migration[3]. In contrast, exogenous addition of GM3 inhibits angiogenesis via inhibition of the binding of VEGF to VEGF receptor (VEGFR)-2 and induction of VEGFR dimerization[34]. In addition, Kim et al. reported that exogenous addition of GM3 inhibits VEGF-induced intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 expression, leading to reduced monocyte adhesion to HUVECs[35] Furthermore, they showed that pre-injection of GM3 in mice inhibits VEGF- and VEGF/tumor necrosis factor alpha (TNFα)-induced expression of adhesion molecules in vein tissues[35]. In human aortic endothelial cells (HAECs), a-series gangliosides GM1 and GD1a and b-series gangliosides are expressed on the cell surface[36]. To identify the specific gangliosides contributing to EC dysfunction in aging, we investigated the effects of changes in individual cell surface gangliosides in HAECs. We found that GM1 expression increases with cellular senescence on the cell surface of HAECs. Increased GM1 levels do not affect the induction of cellular senescence. On the other hand, they lead to a decrease in insulin signaling related to reduced nitric oxide (NO) production. In addition, GM1 expression is high in HAECs derived from elderly people, suggesting its involvement not only in cellular senescence, but also in the decrease in endothelial function that accompanies aging. These results show that GM1 is involved in endothelial function during cellular senescence and aging and is closely linked to vascular disease[37][36].

    Vascular insulin resistance induced by inflammatory cytokines is associated with the initiation and development of vascular diseases. In humans, circulating TNFα levels increase with aging[38], suggesting a correlation between vascular insulin resistance and plasma TNFα levels. We showed in HAECs stimulated with TNFα that GM1 expression levels on cell membranes change depending on time of exposure and concentration of TNFα and are associated with the regulation of the insulin signaling cascade[39]. These results suggest that cell surface GM1 is a key player in the induction of vascular insulin resistance mediated by TNFα during inflammation. Thus, GM1 has great potential as an EC extracellular target for prevention and cure of vascular diseases[37].

    Numerous studies have demonstrated that ECs are capable of undergoing EndMT, a newly recognized type of cellular trans-differentiation[40][41]. EndMT-derived cells have typical mesenchymal morphology and functions, such as acquisition of movement ability and contractile properties. EndMT is considered to participate in the pathogenesis of several cardiovascular diseases. However, to date, no report is available on the involvement of gangliosides in EndMT. Epithelial cells can undergo a process called epithelial-mesenchymal transition (EMT), which is similar to EndMT. In the human epithelial lens cell line HLE-B3, TGF-β1, one of the EMT up-regulators induces higher expression of GM3. In turn, interaction of GM3 with the TGF-β−receptor promotes EMT[42]. Among breast cancer stem cells, a small portion of cells exhibits co-expression of ganglioside GD2 and CD44high/CD24low. GD2 expression is associated with EMT induction[43]. Based on these findings, the contribution of gangliosides to EndMT could be at least speculated. Future studies are needed to clarify the relationship between gangliosides and EndMT and thus, aid the development of novel prevention and therapeutic strategies for vascular diseases.

    3. VSMCs and Gangliosides

    VSMC proliferation is associated with the development and progression of cardiovascular diseases. GD3 has a dual role in modulating proliferation and apoptosis of VSMCs[8], and increased levels of GD3 are known to be associated with atherosclerosis [61]. Overexpression of GD3 attenuates platelet-derived growth factor (PDGF)-induced activation of the extracellular signal-regulated kinase (ERK) pathway and suppresses the proliferation of mouse VSMCs[9]. Furthermore, overexpression of GD3 leads to inhibition of TNFα-induced MMP-9, which is implicated in the progression of atherosclerotic lesions[44]. In addition, several studies have shown the accumulation of GM3 in atherosclerotic lesions[45]. A study carried in mouse VSMCs has shown that TNFα-induced proliferation and induction of MMP-9 are inhibited upon GM3 overexpression. In this study, treatment with anti-GM3 antibodies reversed the inhibitory effects of GM3, indicating that GM3 controls VSMC proliferation and migration during the formation of atherosclerotic lesions [64]. In contrast, in rat aortic VSMCs, exogenous addition of GM1 and GM2, but not GM3, induces activation of the ERK pathway and promotes VSMC proliferation[10].

    VSMCs are not terminally differentiated and can change their phenotype in response to environmental cues, such as growth factors/inhibitors, mechanical influences, cell–cell and cell–matrix interactions, extracellular lipids and lipoproteins, and various inflammatory mediators present in the injured artery wall[46]. Dedifferentiation of VSMCs into macrophage-like cells can be promoted by activation of Krüppel-like factor 4, which is one of the pluripotency transcription factors controlled by PDGF-BB signaling[47][48]. In the neuroblastoma cell line SH-SY5Y, exogenous addition of GM1, GM2, GD1a or GT1b inhibits phosphorylation of the PDGF receptor (PDGFR), resulting in suppressed cell growth, whereas growth inhibition mediated by exogenous GM3 acts downstream of PDGF signal transduction[49]. In Swiss 3T3 cells, overexpression of GM1 by transfection of β4GalNAcT1 and β3GalT4 inhibits PDGF-BB-stimulated growth due to PDGFR dispersion from lipid rafts[50]. Furthermore, exogenous addition of GM1 promotes the osteogenic differentiation of human tendon stem cells via reduction of PDGFR phosphorylation[51]. On the other hand, the contribution of gangliosides to PDGF-BB signaling in VSMCs still has to be clarified, but it could be speculated from the reports cited above that gangliosides are involved in PDGF-BB signaling-mediated dedifferentiation of VSMCs.

    4. Fibroblasts and Gangliosides

    In human fibroblasts derived from fetal lung, GM3 and GD3 are the most commonly expressed gangliosides and their expression decreases in long-term cultures, in which cells undergo senescence[52]. Exogenous GM3 and GD1a promote epithelial growth factor (EGF)- or bFGF-stimulated proliferation of normal human dermal fibroblasts[11]. Additionally, GM3 synthase-deficient skin-derived human fibroblasts exhibit reduction of EGF-stimulated proliferation and migration[12]. In contrast, embryonic fibroblasts derived from GM3 synthase knock-out mice exhibited higher growth potential than wild-type cells due to suppression of the MAPK pathway[14]. GD3 is a structural component of the autophagosome and exogenous administration of GD3 activates autophagy in normal human skin-derived fibroblasts[13]. In rat heart fibroblasts, exogenous GM1 protects from apoptosis through induction of the synthesis of sphingosine 1-phosphate[15]. Despite the functional role of gangliosides in fibroblasts has been demonstrated, the specific type of gangliosides and organs from which fibroblasts originate need to be taken into account. In fact, different organ-derived fibroblasts, such as skin- and oral-derived fibroblasts, exhibit different levels of hyaluronic acid and different growth responses upon TGF-β1 stimulation[53]. Therefore, further functional investigation of gangliosides (particularly in heart-derived fibroblasts) is required to clarify their contribution to cardiovascular diseases.

    During atheromatous plaque formation, myofibroblasts differentiated from fibroblasts elicit collagen deposition and neointimal expansion in the intima. TGF-β1 signaling is known to regulate myofibroblast differentiation[54]. As described above, GM3 and GD2 contribute to TGF-β1 signaling [59,60]. In addition, raft GM1 is important for TGF-β1-stimulated myofibroblast differentiation in human skin-derived fibroblasts[55]. To date, the direct contribution of gangliosides to myofibroblast differentiation has not been clarified. Therefore, further studies are required, although it can be speculated that gangliosides GM3, GM1 and GD2 are involved in myofibroblast differentiation.

    5. Inflammatory Cells and Gangliosides

    In human neutrophils, expression of GSLs is heterogeneous and complex ganglioside mixtures, including GM1 and GM3, exist[16]. Mature neutrophils express the highest levels of GM1[16][17]. Furthermore, when cells undergo apoptosis, expression of GM1 at the cell surface is lost at an early stage. Thus, GM1 is considered a marker for detection of aged neutrophils[18].

    It is well known that GD3 is the most abundantly expressed ganglioside on the surface of almost all mast cells[56]. It has also been shown that elevated expression levels of GM3, GM2, GM1 and GD1a can be observed during maturation of the human mast cell line HMC-1[19] and that exogenous GM3 inhibits interleukin (IL)-3-stimulated cell proliferation of bone marrow-derived mouse mast cells[20]. In addition, it has been reported that cross-linking of GD1b-derived gangliosides activates RBL-2H3, a rat mast cell line, leading to the release of inflammatory cytokines, such as IL-4, IL-6 and TNFα[21].

    Monocytes and macrophages express high levels of GM3 in both humans and mice[57]. Cultured human macrophages yield about seven times the amount of GM3 (per million cells) of peripheral blood monocytes[58]. In the human pre-myeloid leukemia cell line HL-60 and histiocytic lymphoma cell line U937, exogenous GM3 induces monocytic cell differentiation and notably, GM3 increase during macrophage-like cell differentiation[22]. GM3 synthase levels are significantly higher in human monocyte-derived macrophages than in monocytes and GM3 has been considered as a physiological modulator of macrophage differentiation in human atherosclerotic aorta[59]. In bone marrow-derived macrophages, peritoneal macrophages and the Raw264.7 macrophage cell line, exogenous GM1 contributes to the induction of arginase-1, a major M2 macrophage marker, and to the secretion of monocyte chemoattractant protein-1 (MCP-1) through CD206-mediated activation of signal transducer and activator of transcription (STAT) 6[23].

    Human T cells express both GM3 and GM1, which are clustered in lipid rafts and considered to be involved in T cell activation[24]. Furthermore, other gangliosides (GD1a, GD1b, GT1b, etc.) have been detected at minor levels in human T cells[60][61]. It has been demonstrated that GM1 expression is upregulated in human CD8+ T cells upon IL-2 stimulation[25]. In human CD4+ T cells, exogenous GM3 and GM1 downregulate the cell surface expression of CD4, inhibiting lymphocyte function-associated antigen-1-dependent adhesion[26]. In murine T cells, GM3, GM1, GD1b and GD3 are expressed similarly to human T cells. Murine CD4+ T cells express higher levels of ST3GAL5 than CD8+ T cells to synthesize a- and b-series gangliosides (GM1 and GD1b). In contrast, murine CD8+ T cells express more B4galnt1, resulting in higher levels of o-series gangliosides[62].

    Taken together, these data show that gangliosides in inflammatory cells are prominently involved in atherosclerosis.

    6. Other Types of Cells and Gangliosides

    In human platelets, GM3 is major ganglioside and GD3 is synthesized after activation[27]. Additionally, exogenous GM3 and GM1 induce the activation of human platelets, resulting in Ca2+ mobilization and shape change[29]. GD3 selectively stimulates human platelet adhesion, spreading and aggregation[28]. Kim et al. showed that exogenous GD2 induces apoptosis in human platelets by cross-linking Siglec-7[30].

    In 3T3-L1 mouse adipocytes, increased expression of GM3 upon TNFα stimulation induces insulin resistance through interaction between GM3 and the insulin receptor[31]. Furthermore, GM3 expression is elevated upon inflammatory conditions in primary mouse adipocytes and adipose tissues[63]. Insulin resistance in mouse adipocytes causes the production of MCP-1, which recruits monocytes and activates proinflammatory macrophages[64].

    This entry is adapted from 10.3390/ijms20246362

    References

    1. Marco Rusnati; Chiara Urbinati; Elena Tanghetti; Patrizia Dell'era; Hugues Lortat-Jacob; Marco Presta; Cell membrane GM1 ganglioside is a functional coreceptor for fibroblast growth factor 2. Proceedings of the National Academy of Sciences 2002, 99, 4367-4372, 10.1073/pnas.072651899.
    2. Mark Slevin; Shant Kumar; Xiaotong He; John Gaffney; Physiological concentrations of gangliosides gm1, gm2 and gm3 differentially modify basic‐fibroblast‐growth‐factor‐induced mitogenesis and the associated signalling pathway in endothelial cells. International Journal of Cancer 1999, 82, 412-423, 10.1002/(sici)1097-0215(19990730)82:3<412::aid-ijc15>3.3.co;2-a.
    3. Yihui Liu; James McCarthy; Stephan Ladisch; Membrane Ganglioside Enrichment Lowers the Threshold for Vascular Endothelial Cell Angiogenic Signaling. Cancer Research 2006, 66, 10408-10414, 10.1158/0008-5472.can-06-1572.
    4. Tae-Wook Chung; Seok-Jo Kim; Hee-Jung Choi; Keuk-Jun Kim; Mi-Jin Kim; Sung-Hoon Kim; Hyo-Jeong Lee; Jeong-Heon Ko; Young-Choon Lee; Akemi Suzuki; et al. Ganglioside GM3 inhibits VEGF/VEGFR-2-mediated angiogenesis: Direct interaction of GM3 with VEGFR-2. Glycobiology 2008, 19, 229-239, 10.1093/glycob/cwn114.
    5. Kim, S. J1.; Chung, T.W.; Choi, H.J.; Jin, U.H.; Ha, K.T.; Lee, Y.C.; Kim, C.H. Monosialic ganglioside GM3 specifically suppresses the monocyte adhesion to endothelial cells for inflammation. Int. J. Biochem. Cell Biol. 2014, 46, 32–38.
    6. Norihiko Sasaki; Yoko Itakura; Masashi Toyoda; Ganglioside GM1 Contributes to the State of Insulin Resistance in Senescent Human Arterial Endothelial Cells.. Journal of Biological Chemistry 2015, 290, 25475-86, 10.1074/jbc.M115.684274.
    7. Norihiko Sasaki; Yoko Itakura; Masashi Toyoda; 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. Oncotarget 2017, 9, 5562-5577, 10.18632/oncotarget.23726.
    8. Anil Kumar Bhunia; Günter Schwarzmann; Subroto Chatterjee; GD3 Recruits Reactive Oxygen Species to Induce Cell Proliferation and Apoptosis in Human Aortic Smooth Muscle Cells. Journal of Biological Chemistry 2002, 277, 16396-16402, 10.1074/jbc.m200877200.
    9. S.-K. Moon; H.-M. Kim; Y.-C. Lee; C.-H. Kim; Disialoganglioside (GD3) Synthase Gene Expression Suppresses Vascular Smooth Muscle Cell Responses via the Inhibition of ERK1/2 Phosphorylation, Cell Cycle Progression, and Matrix Metalloproteinase-9 Expression. Journal of Biological Chemistry 2004, 279, 33063-33070, 10.1074/jbc.m313462200.
    10. Ioanna Gouni-Berthold; Claudia Seul; Yon Ko; Jürgen Hescheler; Agapios Sachinidis; Gangliosides GM1 and GM2 induce vascular smooth muscle cell proliferation via extracellular signal-regulated kinase 1/2 pathway.. Hypertension 2001, 38, 1030-1037, 10.1161/hy1101.093104.
    11. Ruixiang Li; Jessica Manela; Y. Kong; Stephan Ladisch; Cellular Gangliosides Promote Growth Factor-induced Proliferation of Fibroblasts. Journal of Biological Chemistry 2000, 275, 34213-34223, 10.1074/jbc.m906368199.
    12. Yihui Liu; Yan Su; Max Wiznitzer; Olga Epifano; Stephan Ladisch; Ganglioside depletion and EGF responses of human GM3 synthase-deficient fibroblasts. Glycobiology 2008, 18, 593-601, 10.1093/glycob/cwn039.
    13. Paola Matarrese; Tina Garofalo; Valeria Manganelli; Lucrezia Gambardella; Matteo Marconi; Maria Grasso; Antonella Tinari; Roberta Misasi; Walter Malorni; Maurizio Sorice; et al. Evidence for the involvement of GD3 ganglioside in autophagosome formation and maturation. Autophagy 2014, 10, 750-765, 10.4161/auto.27959.
    14. A Hashiramoto; H Mizukami; T Yamashita; Ganglioside GM3 promotes cell migration by regulating MAPK and c-Fos/AP-1. Oncogene 2006, 25, 3948-3955, 10.1038/sj.onc.1209416.
    15. Lucia Cavallini; Rina Venerando; Giovanni Miotto; Adolfo Alexandre; Ganglioside GM1 Protection from Apoptosis of Rat Heart Fibroblasts. Archives of Biochemistry and Biophysics 1999, 370, 156-162, 10.1006/abbi.1999.1378.
    16. Mark R. Stroud; Kazuko Handa; Mary Ellen K. Salyan; Kazunori Ito; Steven B. Levery; Sen-Itiroh Hakomori; Bruce B. Reinhold; Vernon N. Reinhold; Monosialogangliosides of Human Myelogenous Leukemia HL60 Cells and Normal Human Leukocytes. 2. Characterization of E-Selectin Binding Fractions, and Structural Requirements for Physiological Binding to E-Selectin†. Biochemistry 1996, 35, 770-778, 10.1021/bi952461g.
    17. B A Macher; J C Klock; M N Fukuda; Isolation and structural characterization of human lymphocyte and neutrophil gangliosides.. Journal of Biological Chemistry 1981, 256, , .
    18. Ahmed Sheriff; Udo S. Gaipl; Sandra Franz; Petra Heyder; Reinhard E. Voll; Joachim R. Kalden; Martin Herrmann; Loss of GM1 surface expression precedes annexin V-phycoerythrin binding of neutrophils undergoing spontaneous apoptosis during in vitro aging. Cytometry 2004, 62, 75-80, 10.1002/cyto.a.20090.
    19. T. Zuberbier; S. Guhl; T. Hantke; C. Hantke; P. Welker; J. Grabbe; B. M. Henz; Alterations in ganglioside expression during the differentiation of human mast cells.. Experimental Dermatology 1999, 8, 380-387, 10.1111/j.1600-0625.1999.tb00386.x.
    20. Hidekazu Fujimaki; Osamu Nohara; Noboru Katayama; Tatsuya Abe; Keiko Nohara; Ganglioside GM3 Inhibits lnterleukin-3-Dependent Bone Marrow-Derived Mast Cell Proliferation. International Archives of Allergy and Immunology 1995, 107, 527-532, 10.1159/000237095.
    21. Edismauro Garcia Freitas Filho; Elaine Zayas Marcelino Da Silva; Camila Ziliotto Zanotto; Constance Oliver; Maria Célia Jamur; Cross-Linking Mast Cell Specific Gangliosides Stimulates the Release of Newly Formed Lipid Mediators and Newly Synthesized Cytokines. Mediators of Inflammation 2016, 2016, 1-10, 10.1155/2016/9160540.
    22. H. Nojiri; F. Takaku; Y. Terui; Y. Miura; M. Saito; Ganglioside GM3: an acidic membrane component that increases during macrophage-like cell differentiation can induce monocytic differentiation of human myeloid and monocytoid leukemic cell lines HL-60 and U937.. Proceedings of the National Academy of Sciences 1986, 83, 782-786, 10.1073/pnas.83.3.782.
    23. Tae-Wook Chung; Hee-Jung Choi; Mi-Ju Park; Hee-Jin Choi; Syng-Ook Lee; Keuk-Jun Kim; Cheorl-Ho Kim; Changwan Hong; Kyun-Ha Kim; Myungsoo Joo; et al. The function of cancer-shed gangliosides in macrophage phenotype: involvement with angiogenesis. Oncotarget 2016, 8, 4436-4448, 10.18632/oncotarget.13878.
    24. Günter Rosenfelder; Peter Wernet; Dietmar G. Braun; Andreas Ziegler; Ganglioside Patterns: New Biochemical Markers for Human Hematopoietic Cell Lines. JNCI: Journal of the National Cancer Institute 1982, 68, 203–209, 10.1093/jnci/68.2.203.
    25. Jae-Ho Cho; Hee-Ok Kim; Charles D. Surh; Jonathan Sprent; T cell receptor-dependent regulation of lipid rafts controls naive CD8+ T cell homeostasis.. Immunity 2010, 32, 214-226, 10.1016/j.immuni.2009.11.014.
    26. Christiane Barbat; Maylis Trucy; Maurizio Sorice; Tina Garofalo; Valeria Manganelli; Alain Fischer; Fabienne Mazerolles; p56lck, LFA-1 and PI3K but not SHP-2 interact with GM1- or GM3-enriched microdomains in a CD4–p56lck association-dependent manner. Biochemical Journal 2007, 402, 471-481, 10.1042/bj20061061.
    27. P Ferroni; L Lenti; F Martini; F Ciatti; G M Pontieri; P P Gazzaniga; Ganglioside content of human platelets--differences in resting and activated platelets.. Thrombosis and Haemostasis 1997, 77, , .
    28. Alexey V. Mazurov; Nina V. Prokazova; Irina A. Mikhailenko; Dmitry N. Mukjin; Vadim S. Repin; Lev D. Bergelson; Stimulation of platelet adhesion and activation by ganglioside GD3 adsorbed to plastic. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1988, 968, 167-171, 10.1016/0167-4889(88)90004-3.
    29. Yutaka Yatomi; Yasuyuki Igarashi; Sen-Itiroh Hakomori; Effects of exogenous gangliosides on intracellular Ca 2+ mobilization and functional responses in human platelets. Glycobiology 1996, 6, 347-353, 10.1093/glycob/6.3.347.
    30. Kim Anh Nguyen; Hind Hamzeh-Cognasse; Sabine Palle; Isabelle Anselme-Bertrand; Charles-Antoine Arthaud; Patricia Chavarin; Bruno Pozzetto; Olivier Garraud; Fabrice Cognasse; Role of Siglec-7 in Apoptosis in Human Platelets. PLOS ONE 2014, 9, e106239, 10.1371/journal.pone.0106239.
    31. Kazuya Kabayama; Takashige Sato; Kumiko Saito; Nicoletta Loberto; Alessandro Prinetti; Sandro Sonnino; Masataka Kinjo; Yasuyuki Igarashi; Jin-Ichi Inokuchi; Dissociation of the insulin receptor and caveolin-1 complex by ganglioside GM3 in the state of insulin resistance. Proceedings of the National Academy of Sciences 2007, 104, 13678-13683, 10.1073/pnas.0703650104.
    32. Sevim Duvar; Jasna Peter-Katalinić; Franz-Georg Hanisch; Johannes Müthing; Isolation and structural characterization of glycosphingolipids of in vitro propagated bovine aortic endothelial cells.. Glycobiology 1997, 7, 1099-1109, 10.1093/glycob/7.8.1099.
    33. Mark Slevin; Shant Kumar; Xiaotong He; John Gaffney; Physiological concentrations of gangliosides gm1, gm2 and gm3 differentially modify basic-fibroblast-growth-factor-induced mitogenesis and the associated signalling pathway in endothelial cells. International Journal of Cancer 1999, 82, 412-423, 10.1002/(sici)1097-0215(19990730)82:3<412::aid-ijc15>3.0.co;2-j.
    34. Tae-Wook Chung; Seok-Jo Kim; Hee-Jung Choi; Keuk-Jun Kim; Mi-Jin Kim; Sung-Hoon Kim; Hyo-Jeong Lee; Jeong-Heon Ko; Young-Choon Lee; Akemi Suzuki; et al. Ganglioside GM3 inhibits VEGF/VEGFR-2-mediated angiogenesis: Direct interaction of GM3 with VEGFR-2. Glycobiology 2008, 19, 229-239, 10.1093/glycob/cwn114.
    35. Seok-Jo Kim; Tae-Wook Chung; Hee-Jung Choi; Un-Ho Jin; Ki-Tae Ha; Young-Choon Lee; Cheorl-Ho Kim; Monosialic ganglioside GM3 specifically suppresses the monocyte adhesion to endothelial cells for inflammation. The International Journal of Biochemistry & Cell Biology 2014, 46, 32-38, 10.1016/j.biocel.2013.09.015.
    36. Norihiko Sasaki; Yoko Itakura; Masashi Toyoda; Ganglioside GM1 Contributes to the State of Insulin Resistance in Senescent Human Arterial Endothelial Cells.. Journal of Biological Chemistry 2015, 290, 25475-86, 10.1074/jbc.M115.684274.
    37. Norihiko Sasaki; Yoko Itakura; Masashi Toyoda; Gangliosides Contribute to Vascular Insulin Resistance.. International Journal of Molecular Sciences 2019, 20, 1819, 10.3390/ijms20081819.
    38. Paola Lucia Minciullo; Antonino Catalano; Giuseppe Mandraffino; Marco Casciaro; Andrea Crucitti; Giuseppe Maltese; Nunziata Morabito; Antonino Lasco; Sebastiano Gangemi; Giorgio Basile; et al. Inflammaging and Anti-Inflammaging: The Role of Cytokines in Extreme Longevity. Archivum Immunologiae et Therapiae Experimentalis 2015, 64, 111-126, 10.1007/s00005-015-0377-3.
    39. Norihiko Sasaki; Yoko Itakura; Masashi Toyoda; 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. Oncotarget 2017, 9, 5562-5577, 10.18632/oncotarget.23726.
    40. Ampadu O. Jackson; Jingjing Zhang; Zhisheng Jiang; Kai Yin; Endothelial-to-mesenchymal transition: A novel therapeutic target for cardiovascular diseases. Trends in Cardiovascular Medicine 2017, 27, 383-393, 10.1016/j.tcm.2017.03.003.
    41. Kovacic, J.C.; Dimmeler, S.; Harvey, R.P.; Finkel, T.; Aikawa, E.; Krenning, G.; Baker, A.H. Endothelial to Mesenchymal Transition in Cardiovascular Disease: JACC State-of-the-Art Review. J. Am. Coll. Cardiol. 2019, 73, 190–209.
    42. Seok-Jo Kim; Tae-Wook Chung; Hee-Jung Choi; Choong-Hwan Kwak; Kwon-Ho Song; Seok-Jong Suh; Kyung-Min Kwon; Young-Chae Chang; Young-Guk Park; Hyeun Wook Chang; et al. Ganglioside GM3 participates in the TGF-β1-induced epithelial–mesenchymal transition of human lens epithelial cells. Biochemical Journal 2012, 449, 241-251, 10.1042/bj20120189.
    43. Venkata Lokesh Battula; Yuexi Shi; Kurt W. Evans; Rui-Yu Wang; Erika L. Spaeth; Rodrigo O. Jacamo; Rudy Guerra; Aysegul A. Sahin; Frank C. Marini; Gabriel Hortobagyi; et al. Ganglioside GD2 identifies breast cancer stem cells and promotes tumorigenesis.. Journal of Clinical Investigation 2012, 122, 2066-78, 10.1172/JCI59735.
    44. Thomas P Vacek; Shahnaz Rehman; Diana Neamtu; Shipeng Yu; Srikanth Givimani; Suresh C Tyagi; Matrix metalloproteinases in atherosclerosis: role of nitric oxide, hydrogen sulfide, homocysteine, and polymorphisms. Vascular Health and Risk Management 2015, 11, 173-183, 10.2147/VHRM.S68415.
    45. Yuri V. Bobryshev; Natalia K. Golovanova; Dinh Tran; Nelya N. Samovilova; Elena V. Gracheva; Eugene E. Efremov; Alexander Y. Sobolev; Yulia V. Yurchenko; Reginald S.A. Lord; Weiping Cao; et al. Expression of GM3 synthase in human atherosclerotic lesions. Atherosclerosis 2006, 184, 63-71, 10.1016/j.atherosclerosis.2005.04.019.
    46. Sima Allahverdian; Chiraz Chaabane; Kamel Boukais; Gordon A Francis; Marie-Luce Bochaton-Piallat; Smooth muscle cell fate and plasticity in atherosclerosis. Cardiovascular Research 2018, 114, 540-550, 10.1093/cvr/cvy022.
    47. Rebecca A. Deaton; Qiong Gan; Gary K. Owens; Sp1-dependent activation of KLF4 is required for PDGF-BB-induced phenotypic modulation of smooth muscle.. American Journal of Physiology-Heart and Circulatory Physiology 2009, 296, H1027-37, 10.1152/ajpheart.01230.2008.
    48. Matthew R. Alexander; Gary K. Owens; Epigenetic Control of Smooth Muscle Cell Differentiation and Phenotypic Switching in Vascular Development and Disease. Annual Review of Physiology 2012, 74, 13-40, 10.1146/annurev-physiol-012110-142315.
    49. Dianna L. Hynds; Monica Summers; James Van Brocklyn; M. Sue O'dorisio; Allan J. Yates; Gangliosides Inhibit Platelet-Derived Growth Factor-Stimulated Growth, Receptor Phosphorylation, and Dimerization in Neuroblastoma SH-SY5Y Cells. Journal of Neurochemistry 2002, 65, 2251-2258, 10.1046/j.1471-4159.1995.65052251.x.
    50. Teruhiko Mitsuda; Keiko Furukawa; Satoshi Fukumoto; Hiroshi Miyazaki; Takeshi Urano; Koichi Furukawa; Overexpression of Ganglioside GM1 Results in the Dispersion of Platelet-derived Growth Factor Receptor from Glycolipid-enriched Microdomains and in the Suppression of Cell Growth Signals. Journal of Biological Chemistry 2002, 277, 11239-11246, 10.1074/jbc.m107756200.
    51. Sonia Bergante; Pasquale Creo; Marco Piccoli; Andrea Ghiroldi; Alessandra Menon; Federica Cirillo; Paola Rota; Michelle M. Monasky; Giuseppe Ciconte; Carlo Pappone; et al. GM1 Ganglioside Promotes Osteogenic Differentiation of Human Tendon Stem Cells. Stem Cells International 2018, 2018, 1-8, 10.1155/2018/4706943.
    52. Takako Ohsawa; Yoshitaka Nagai; Ganglioside changes during cell aging in human diploid fibroblast tig-1. Experimental Gerontology 1982, 17, 287-293, 10.1016/0531-5565(82)90018-3.
    53. Soma Meran; Ng Dong Luo; Russell Simpson; John Martin; Alan Wells; Robert Steadman; Aled O. Phillips; Hyaluronan Facilitates Transforming Growth Factor-β1-dependent Proliferation via CD44 and Epidermal Growth Factor Receptor Interaction. Journal of Biological Chemistry 2011, 286, 17618-17630, 10.1074/jbc.m111.226563.
    54. Adam C. Midgley; Mathew Rogers; Maurice B. Hallett; Aled Clayton; Timothy Bowen; Aled O. Phillips; Robert Steadman; Transforming Growth Factor-β1 (TGF-β1)-stimulated Fibroblast to Myofibroblast Differentiation Is Mediated by Hyaluronan (HA)-facilitated Epidermal Growth Factor Receptor (EGFR) and CD44 Co-localization in Lipid Rafts*. Journal of Biological Chemistry 2013, 288, 14824-14838, 10.1074/jbc.M113.451336.
    55. Norihiko Sasaki; Yoko Itakura; Masashi Toyoda; Sialylation regulates myofibroblast differentiation of human skin fibroblasts.. Stem Cell Research & Therapy 2017, 8, 81, 10.1186/s13287-017-0534-1.
    56. Shunlin Ren; Naotomo Kambe; Zhongmin Du; Yongli Li; Han-Zhang Xia; Michiyo Kambe; Erhard Bieberich; Andrea Pozez; Margaret Grimes; Robert K. Yu; et al. Disialoganglioside GD3 is selectively expressed by developing and mature human mast cells. Journal of Allergy and Clinical Immunology 2001, 107, 322-330, 10.1067/mai.2001.112272.
    57. Senitiroh Hakomori; Structure, organization, and function of glycosphingolipids in membrane.. Current Opinion in Hematology 2003, 10, 16-24, 10.1097/00062752-200301000-00004.
    58. E. V. Gracheva; N. N. Samovilova; N. K. Golovanova; E. R. Andreeva; I. V. Andrianova; E. M. Tararak; N. V. Prokazova; Activation of ganglioside GM3 biosynthesis in human monocyte/macrophages during culturing in vitro.. Biochemistry (Moscow) 2007, 72, 772-777, 10.1134/s0006297907070127.
    59. Elena V. Gracheva; Nelya N. Samovilova; Natalia K. Golovanova; Svetlana V. Kashirina; Alexander Shevelev; Igor Rybalkin; Tat’Yana Gurskaya; Tat’Yana N. Vlasik; Elena R. Andreeva; Nina V. Prokazova; et al. Enhancing of GM3 synthase expression during differentiation of human blood monocytes into macrophages as in vitro model of GM3 accumulation in atherosclerotic lesion. Molecular and Cellular Biochemistry 2009, 330, 121-129, 10.1007/s11010-009-0125-2.
    60. M Sorice; I Parolini; T Sansolini; T Garofalo; V Dolo; M Sargiacomo; T Tai; C Peschle; M R Torrisi; A Pavan; et al. Evidence for the existence of ganglioside-enriched plasma membrane domains in human peripheral lymphocytes.. Journal of Lipid Research 1997, 38, , .
    61. Tina Garofalo; A Novel Mechanism of CD4 Down-modulation Induced by Monosialoganglioside GM3. INVOLVEMENT OF SERINE PHOSPHORYLATION AND PROTEIN KINASE C delta TRANSLOCATION. Journal of Biological Chemistry 1998, 273, 35153-35160, 10.1074/jbc.273.52.35153.
    62. Tao Zhang; Antonius A. De Waard; Manfred Wuhrer; Robbert M. Spaapen; The Role of Glycosphingolipids in Immune Cell Functions. Frontiers in Immunology 2019, 10, 90, 10.3389/fimmu.2019.00090.
    63. Masakazu Nagafuku; Takashige Sato; Saya Sato; Kyoko Shimizu; Toshio Taira; Jin-Ichi Inokuchi; Control of homeostatic and pathogenic balance in adipose tissue by ganglioside GM3. Glycobiology 2014, 25, 303-318, 10.1093/glycob/cwu112.
    64. Mitsugu Shimobayashi; Verena Albert; Bettina Woelnerhanssen; Irina C. Frei; Diana Weissenberger; Anne Christin Meyer-Gerspach; Nicolas Clément; Suzette Moes; Marco Colombi; Jerome A. Meier; et al. Insulin resistance causes inflammation in adipose tissue.. Journal of Clinical Investigation 2018, 128, 1538-1550, 10.1172/JCI96139.
    65. Tina Garofalo; A Novel Mechanism of CD4 Down-modulation Induced by Monosialoganglioside GM3. INVOLVEMENT OF SERINE PHOSPHORYLATION AND PROTEIN KINASE C delta TRANSLOCATION. Journal of Biological Chemistry 1998, 273, 35153-35160, 10.1074/jbc.273.52.35153.
    66. Mitsugu Shimobayashi; Verena Albert; Bettina Woelnerhanssen; Irina C. Frei; Diana Weissenberger; Anne Christin Meyer-Gerspach; Nicolas Clément; Suzette Moes; Marco Colombi; Jerome A. Meier; et al. Insulin resistance causes inflammation in adipose tissue.. Journal of Clinical Investigation 2018, 128, 1538-1550, 10.1172/JCI96139.
    More