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

Abstract

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.

Deregulation of sphingolipid metabolism in Alzheimer's disease

“…The ceramide-enriched platforms cluster receptor molecules, transmit apoptotic stimuli into the cell, and eventually cause cell death (Bollinger et al, 2005;Gulbins, 2003). ASM is most active in an acidic environment (pH 4.5), but it can also function at neutral pH (7.0) (Schissel et al, 1998), consistent with its movement to the plasma membrane.…”

Novel first-dose adverse drug reactions during a phase I trial of olipudase alfa (recombinant human acid sphingomyelinase) in adults with Niemann–Pick disease type B (acid sphingomyelinase deficiency)

“…Despite plasma sphingomyelin concentrations being normal in patients, intravascular sources of sphingomyelin could still contribute to the increase in plasma ceramide that occurred within hours of the infusion because olipudase alfa retains a low level of activity at a neutral pH (Genzyme data on file) and has an unusually long circulating t 1/2 for an ERT (10-15 h vs. <10 min to 4 h for other ERTs). The slow clearance of olipudase alfa from the circulation may be a result of its binding to lipoprotein particles or cell membranes 20 and/or impaired targetcell uptake via mannose-6-phosphate receptors. 21 Interestingly, the types of ADRs observed upon first exposure to olipudase alfa have not been reported in patients with Gaucher disease receiving imiglucerase ERT, even though ceramide is a catabolite of glucosylceramide, the enzyme substrate.…”

Recent advances in the immunobiology of ceramide

“…Sphingomyelinase-mediated hydrolysis results in an increased efflux of cholesterol from LDL. Exogenous cell-permeable ceramide induces cardiomyocyte apoptosis in vitro, which contributes to myocardial ischemia/reperfusion injury (Soeda et al, 1995;Galle et al, 1991;Leventhal et al, 2001;Schissel et al, 1998;Bielawska et al, 1997). Induction of endothelial dysfunction in small coronary arteries by ceramide occurs via NADPH oxidase-mediated superoxide production and subsequent increase in peroxynitrite.…”