Oxidized low density lipoprotein stimulates aortic smooth muscle cell proliferation

Chatterjee, Subroto; Ghosh, Nabendu

doi:10.1093/glycob/6.3.303

Cited by 62 publications

(39 citation statements)

References 11 publications

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“…Because VEGF induced LacCer synthase activity, we first used D-PDMP, initially shown to be an inhibitor of GlcCer synthase 31 but later proven to be an inhibitor of purified LacCer synthase. 28,32 Our studies provided evidence that VEGF-induced LacCer/GlcCer synthesis, PECAM-1 gene/protein expression, and angiogenesis was inhibited by D-PDMP in a dose-dependent fashion. Moreover, this inhibitory effect was by passed by LacCer but not GlcCer, suggesting that VEGF targets the LacCer synthase to induce angiogenesis.…”

Section: Discussionmentioning

confidence: 75%

Novel Role of Lactosylceramide in Vascular Endothelial Growth Factor–Mediated Angiogenesis in Human Endothelial Cells

Rajesh

Kolmakova

Chatterjee

2005

Circulation Research

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Abstract-Vascular endothelial growth factor (VEGF) has been implicated in angiogenesis associated with coronary heart disease, vascular complications in diabetes, inflammatory vascular diseases, and tumor metastasis. The mechanism of VEGF-driven angiogenesis involving glycosphingolipids such as lactosylceramide (LacCer), however, is not known. To demonstrate the involvement of LacCer in VEGF-induced angiogenesis, we used small interfering RNA (siRNA)-mediated silencing of LacCer synthase expression (GalT-V) in human umbilical vein endothelial cells. This gene silencing markedly inhibited VEGF-induced platelet endothelial cell adhesion molecule-1 (PECAM-1) expression and angiogenesis. Second, we used D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of LacCer synthase and glucosylceramide synthase, that significantly mitigated VEGF-induced PECAM-1 expression and angiogenesis. Interestingly, these phenotypic changes were reversed by LacCer but not by structurally related compounds such as glucosylceramide, digalactosylceramide, and ceramide. In a human mesothelioma cell line (REN) that lacks the endogenous expression of PECAM-1, VEGF/LacCer failed to stimulate PECAM-1 expression and tube formation/angiogenesis. In REN cells expressing human PECAM-1 gene/protein, however, both VEGF and LacCerinduced PECAM-1 protein expression and tube formation /angiogenesis. In fact, VEGF-induced but not LacCerinduced angiogenesis was mitigated by SU-1498, a VEGF receptor tyrosine kinase inhibitor. Also, VEGF/LacCerinduced PECAM-1 expression and angiogenesis was mitigated by protein kinase C and phospholipase A 2 inhibitors. These results indicate that LacCer generated in VEGF-treated endothelial cells may serve as an important signaling molecule for PECAM-1 expression and in angiogenesis. This finding and the reagents developed in our report may be useful as anti-angiogenic drugs for further studies in vitro and in vivo. Key Words: vascular endothelial growth factor Ⅲ lactosylceramide Ⅲ platelet endothelial cell adhesion molecule-1 Ⅲ angiogenesis V ascular endothelial growth factor (VEGF) has been implicated in the process of vasculogenesis and angiogenesis. 1,2 Aberrant expression of VEGF has been reported in several vascular pathologies such as inflammation, complications of diabetes mellitus, cardiovascular diseases, and tumor metastasis. 3 VEGF binds to its receptors KDR/Flk-1 to mediate its effect on angiogenesis in physiological conditions and in human atherosclerosis. 4 -6 Platelet endothelial cell adhesion molecule-1 (PECAM-1)/ CD31 is a constitutively expressed integral protein in endothelial cells. 7 In addition, PECAM-1 is expressed in platelets, monocytes, neutrophils, and a certain subset of T cells. 8 Recent studies implicate PECAM-1 in angiogenesis and in vitro endothelial cell migration. 9,10 For example, human mesothelioma cell line (REN) that is deficient in PECAM-1 10 and cells from PECAM-1 deficient mice 11 did not form tubes in vitro (angiogenesis). In contrast, REN cells overe...

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Section: Discussionmentioning

confidence: 75%

Novel Role of Lactosylceramide in Vascular Endothelial Growth Factor–Mediated Angiogenesis in Human Endothelial Cells

Rajesh

Kolmakova

Chatterjee

2005

Circulation Research

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“…45 This appeared to be a specific effect of Ox-LDL, since Ox-LDL did not stimulate the activity of GlcT-1 and/or the activities of other relevant catabolic enzymes in GSL metabolism ( Figure 1). Preincubation of ASMCs with an antibody against either Ox-LDL or GalT-2 compromised Ox-LDL-mediated activation of GalT-2 and cell proliferation.…”

Section: Effect Of Ox-ldl On Galt-2 and Laccermentioning

confidence: 91%

“…Preincubation of ASMCs with an antibody against either Ox-LDL or GalT-2 compromised Ox-LDL-mediated activation of GalT-2 and cell proliferation. 45 Next, it was shown that LacCer itself markedly stimulated the proliferation of ASMCs. 46 To substantiate these studies further, we used an inhibitor D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) (Figure 2).…”

Section: Effect Of Ox-ldl On Galt-2 and Laccermentioning

confidence: 99%

Sphingolipids in Atherosclerosis and Vascular Biology

Chatterjee

1998

ATVB

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221

182

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Abstract-Sphingolipids and their metabolic products are now known to have second-messenger functions in a variety of cellular signaling pathways. Lactosylceramide (LacCer), a glycosphingolipid (GSL) present in vascular cells such as endothelial cells, smooth muscle cells, macrophages, neutrophils, platelets, and monocytes, contributes to atherosclerosis. Large amounts of LacCer accumulate in fatty streaks, intimal plaque, and calcified intimal plaque, along with oxidized low density lipoproteins (Ox-LDLs), growth factors, and proinflammatory cytokines. A possible role for LacCer in vascular cell biology was suggested when this GSL was found to stimulate the proliferation in vitro of aortic smooth muscle cells (ASMCs). A further link of LacCer in atherosclerosis was uncovered by the finding that Ox-LDLs stimulated specifically the biosynthesis of LacCer. Ox-LDL-stimulated endogenous synthesis of LacCer by activation of UDP-Gal:GlcCer,␤1-4galtransferase (GalT-2) is an early step in this signaling pathway. In turn, LacCer serves as a lipid second messenger that orchestrates a signal transduction pathway, ultimately leading to cell proliferation. This signaling pathway includes LacCer-mediated activation of NADPH oxidase that produces superoxide. Such superoxide molecules stimulate the GTP loading of p21 ras . Subsequently, the kinase cascade ( T hudichum 1 first discovered cerebroside from the human brain in 1884. A characteristic component of this and all glycosphingolipids (GSLs) is an aliphatic amino alcohol, sphingosine. Thudichum called this compound sphingosine because of its enigmatic chemical nature (containing both amine and alcohol groups, but insoluble in water), referring to the Sphinx of Greek mythology who posed riddles. Since that time, most of the studies on sphingoglycolipids have been pursued in regard to determining their structure, biosynthesis, and degradation. These compounds might have been forgotten had it not been shown that the inability to catabolize certain GSLs resulted in their accumulation in various tissues, leading to metabolic diseases, 2 collectively called the "glycosphingo-

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“…Studies by Chatterjee et al 18,19 have also shown that the biosynthesis of lactosylceramide from glucosylceramide is regulated by LDL and ox-LDL levels. Higher levels of LDL suppress lactosylceramide synthase, an enzyme promoting synthesis of more complex glycosphingolipids from glucosylceramide (Figure 1), which thereby inhibits synthesis of lactosylceramide from glucosylceramide.…”

Section: Sphingolipids Neutral Lipids and Ox-ldlmentioning

confidence: 95%

Sphingolipids Contribute to Human Atherosclerotic Plaque Inflammation

Edsfeldt

Dunér

Ståhlman

et al. 2016

ATVB

155

127

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Objective-Lipids are central to the development of atherosclerotic plaques. Specifically, which lipids are culprits remains controversial, and promising targets have failed in clinical studies. Sphingolipids are bioactive lipids present in atherosclerotic plaques, and they have been suggested to have both proatherogenic and antiatherogenic. However, the biological effects of these lipids remain unknown in the human atherosclerotic plaque. The aim of this study was to assess plaque levels of sphingolipids and investigate their potential association with and contribution to plaque vulnerability. Approach and Results-Glucosylceramide, lactosylceramide, ceramide, dihydroceramide, sphingomyelin, and sphingosine-1-phosphate were analyzed in homogenates from 200 human carotid plaques using mass spectrometry. Inflammatory activity was determined by analyzing plaque levels of cytokines and plaque histology. Caspase-3 was analyzed by ELISA technique. Expression of regulatory enzymes was analyzed with RNA sequencing. Human coronary artery smooth muscle cells were used to analyze the potential role of the 6 sphingolipids as inducers of plaque inflammation and cellular apoptosis in vitro. All sphingolipids were increased in plaques associated with symptoms and correlated with inflammatory cytokines. All sphingolipids, except sphingosine-1-phosphate, also correlated with histological markers of plaque instability. Lactosylceramide, ceramide, sphingomyelin, and sphingosine-1-phosphate correlated with caspase-3 activity. In vitro experiments revealed that glucosylceramide, lactosylceramide, and ceramide induced cellular apoptosis. All analyzed sphingolipids induced an inflammatory response in human coronary artery smooth muscle cells. Conclusions-This

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Oxidized low density lipoprotein stimulates aortic smooth muscle cell proliferation

Cited by 62 publications

References 11 publications

Novel Role of Lactosylceramide in Vascular Endothelial Growth Factor–Mediated Angiogenesis in Human Endothelial Cells

Novel Role of Lactosylceramide in Vascular Endothelial Growth Factor–Mediated Angiogenesis in Human Endothelial Cells

Sphingolipids in Atherosclerosis and Vascular Biology

Sphingolipids Contribute to Human Atherosclerotic Plaque Inflammation

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