Modified low density lipoprotein delivers substrate for ceramide formation and stimulates the sphingomyelin‐ceramide pathway in human macrophages

Kinscherf, Ralf; Claus, Ralf A.; Deigner, Hans Peter; Nauen, Olaf; Gehrke, Christoph; Hermetter, Albin; Russwurm, S.; Daniel, Volker; Hack, Volker; Metz, J.

doi:10.1016/s0014-5793(97)00157-9

Cited by 44 publications

(32 citation statements)

References 33 publications

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“…One theoretical possibility is that SMase-treated lipoproteins may be able to deliver ceramide to cells and induce certain ceramide-mediated signal transduction events (63)(64)(65)(66). In fact, oxidized LDL-induced stimulation of smooth muscle cell proliferation may involve the ceramide signaling pathway (67).…”

Section: Discussionmentioning

confidence: 99%

Secretory Sphingomyelinase, a Product of the Acid Sphingomyelinase Gene, Can Hydrolyze Atherogenic Lipoproteins at Neutral pH

Schissel¹,

Jiang²,

Tweedie-Hardman³

et al. 1998

Journal of Biological Chemistry

303

263

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The subendothelial aggregation and retention of low density lipoprotein (LDL) are key events in atherogenesis, but the mechanisms in vivo are not known. Previous studies have shown that treatment of LDL with bacterial sphingomyelinase (SMase) in vitro leads to the formation of lesion-like LDL aggregates that become retained on extracellular matrix and stimulate macrophage foam cell formation. In addition, aggregated human lesional LDL, but not unaggregated lesional LDL or plasma LDL, shows evidence of hydrolysis by an arterial wall SMase in vivo, and several arterial wall cell types secrete a SMase (S-SMase). S-SMase, however, has a sharp acid pH optimum using a standard in vitro SMmicelle assay. Thus, a critical issue regarding the potential role of S-SMase in atherogenesis is whether the enzyme can hydrolyze lipoprotein-SM, particularly at neutral pH. We now show that S-SMase can hydrolyze and aggregate native plasma LDL at pH 5.5 but not at pH 7.4. Remarkably, LDL modified by oxidation, treatment with phospholipase A 2 , or enrichment with apolipoprotein CIII, which are modifications associated with increased atherogenesis, is hydrolyzed readily by S-SMase at pH 7.4. In addition, lipoproteins from the plasma of apolipoprotein E knock-out mice, which develop extensive atherosclerosis, are highly susceptible to hydrolysis and aggregation by S-SMase at pH 7.4; a high SM:PC ratio in these lipoproteins appears to be an important factor in their susceptibility to S-SMase. Most importantly, LDL extracted from human atherosclerotic lesions, which is enriched in sphingomyelin compared with plasma LDL, is hydrolyzed by S-SMase at pH 7.4 10-fold more than same donor plasma LDL, suggesting that LDL is modified in the arterial wall to increase its susceptibility to S-SMase. In summary, atherogenic lipoproteins are excellent substrates for S-SMase, even at neutral pH, making this enzyme a leading candidate for the arterial wall SMase that hydrolyzes LDL-SM and causes subendothelial LDL aggregation.

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Section: Discussionmentioning

confidence: 99%

Secretory Sphingomyelinase, a Product of the Acid Sphingomyelinase Gene, Can Hydrolyze Atherogenic Lipoproteins at Neutral pH

Schissel¹,

Jiang²,

Tweedie-Hardman³

et al. 1998

Journal of Biological Chemistry

303

263

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“…Exposure of human blood macrophages to LDL, especially its oxidized or acetylated form, induced a 40% elevation of the endogenous level of ceramide by increasing both neutral and acidic sphingomyelinase activity (42). Both native and oxidized LDL have been demonstrated to induce sphingomyelin hydrolysis in smooth muscle cells (43).…”

Section: Discussionmentioning

confidence: 99%

Sphingomyelinase Activity Associated with Human Plasma Low Density Lipoprotein

Holopainen¹,

Peñate-Medina

Metso

et al. 2000

Journal of Biological Chemistry

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“…Because HDL and apoAI inhibit PLC-like activity of LDL(-), the formation of cell mediators such as ceramide or other products of this activity could be avoided. These products could be generated by hydrolysis of phospholipids from LDL(-) itself or from the cell membrane as reported in the case of other modifi ed LDL ( 35 ). Moreover, PLC-like activity would be favored in the incubation with monocytes, because enzymatic activity increases at 37°C, thereby increasing the production of infl ammatory cell mediators.…”

Section: Aggregation and Pg Bindingmentioning

confidence: 97%