Sphingolipids in Atherosclerosis and Vascular Biology

Abstract

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-

Ceramide: A common pathway for atherosclerosis?

“…Recent studies have shown that ceramide stimulates the production of ROS in human endothelial cells [58]. Superoxide production was noted to be stimulated 4-fold when aortic smooth muscle cells were incubated with lactosylceramide (LacCer) [14]. Similarly, Yeh et al noted that the only analogue of ceramide to induce superoxide generation was LacCer, via a plasma membrane associated NADPH oxidase [59].…”

“…They are not found in a free form in plasma, but rather are associated with lipoproteins and are particularly abundant in LDL [14]. Additionally, sphingolipids have not been found in lipoprotein deficient plasma, but have been associated with LDL in both normal subjects and patients with familial hypercholesterolemia [15,16].…”

Recent advances in the immunobiology of ceramide

“…Preincubation of cells with the antioxidant Nacetylcysteine (NAC) was found to completely abolish the shear-induced superoxide production and significantly inhibit the ICAM-1 expression. Also, D-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), attenuates the shear-induced activation of GalT-2, superoxide production and ICAM-1 expression (Yeh et al, 2001;Chatterjee, 1998). The triggering of an inflammatory reaction following activation of transcription factors NF-κB and AP-1 causes phenotypic modulation of medial vascular smooth muscle cells and their migration and subsequent proliferation in the intimal layer; increased extracellular matrix production by these vascular smooth muscle cells increases the volume of intimal tissue causing neointimal hyperplasia, ultimately leading to restenosis (Krueger et al, 2006;Mitra and Agrawal, 2006).…”

Ceramide-induced activation of NADPH oxidase and endothelial dysfunction in small coronary arteries

“…We conclude that NADPH oxidase-mediated superoxide production and subsequent peroxynitrite formation mediate ceramide-induced endothelial dysfunction in small coronary arteries. lipids; vasorelaxation; endothelium; signal transduction; free radicals; nitric oxide CERAMIDE, a sphingolipid, has been reported to serve as a signaling molecule in different cell types, including vascular endothelial cells, where it is involved in the regulation of numerous cellular processes, such as ion channel activity, endothelial cell proliferation and apoptosis, and vasomotor responses (7,15,16,19,27). With respect to vasomotor regulation, previous studies from our laboratory have shown that ceramide attenuates endothelium-dependent vasorelaxation in bovine small coronary arteries, which is associated with an increase in superoxide (O 2 Ϫ ⅐) production and a subsequent decrease in nitric oxide (NO) concentrations in vascular endothelial cells (31).…”