Rabbit aorta and human atherosclerotic lesions hydrolyze the sphingomyelin of retained low-density lipoprotein. Proposed role for arterial-wall sphingomyelinase in subendothelial retention and aggregation of atherogenic lipoproteins.

Abstract

Aggregation and retention of LDL in the arterial wall are key events in atherogenesis, but the mechanisms in vivo are not known. Previous work from our laboratories has shown that exposure of LDL to bacterial sphingomyelinase (SMase) in vitro leads to the formation of LDL aggregates that can be retained by extracellular matrix and that are able to stimulate macrophage foam cell formation. We now provide evidence that retained LDL is hydrolyzed by an arterial-wall SMase activity. First, we demonstrated that SMase-induced aggregation is caused by an increase in particle ceramide content, even in the presence of excess sphingomyelin (SM). This finding is compatible with previous data showing that lesional LDL is enriched in SM, though its ceramide content has not previously been reported. To address this critical compositional issue, the ceramide content of lesional LDL was assayed and, remarkably, found to be 10-50-fold enriched compared with plasma LDL ceramide. Furthermore, the ceramide was found exclusively in lesional LDL that was aggregated; unaggregated lesional LDL, which accounted for 20-25% of the lesional material, remained ceramide poor. When

Ceramide: A common pathway for atherosclerosis?

“…The accumulation of sphingolipids noted in atherosclerosis appears to influence the atherogenic process by affecting lipoprotein metabolism and lipid efflux and by acting as a key signaling molecule. This fact is well illustrated by Schissel et al [2], who found a 10 to 50-fold higher content of ceramide (the backbone of all sphingolipids) in low density lipoproteins (LDL) of atherosclerotic lesions when compared with plasma LDL. Additionally, Li et al showed that feeding mice with a sphingolipid-rich diet produces significantly greater atherosclerotic lesions in aortic specimens [3].…”

“…Experimental data support the role of lipoprotein sphingomyelin and arterial SMase in atherogenesis. Sphingomyelin, which is transported into the arterial wall by atherogenic lipoproteins, is in turn affected by arterial wall SMase, increasing in ceramide content and promoting lipoprotein aggregation [2]. LDL extracted from human atherosclerotic lesions is highly enriched in sphingomyelin compared with plasma LDL [12,13].…”

“…Schissel et al analyzed plaque harvested during standard reconstructive surgery for abdominal aortic aneurysms, and found that ceramide was elevated in the areas of aggregated LDL (10-50 fold higher than plasma LDL) and was 2-3 fold higher than that in early human atherosclerotic streaks of the aorta of a 43-year old heart donor [2]. More studies on the analysis of human atherosclerotic plaques revealed that the plaque glycolipids consisted mainly of glucosylceramide and also contained appreciable amounts of lactosylceramide which was completely absent in the unaffected intima [17].…”

“…More studies on the analysis of human atherosclerotic plaques revealed that the plaque glycolipids consisted mainly of glucosylceramide and also contained appreciable amounts of lactosylceramide which was completely absent in the unaffected intima [17]. In animal models of atherosclerosis, ceramide contents were significantly increased in atherosclerotic plaques than the normal vascular wall [2,18]. Modifications in LDL including oxidation to ox-LDL and sphingomyelin enrichment can alter the lipoprotein surface, which may in turn affect the atherosclerotic process.…”

The yins and yangs of ceramide

“…Moreover, increase in ceramide by TNFa inhibited protein phosphatase-1 activation, resulting in a loss of glucose uptake and storage, and contributing to the overall pathology of diabetes [45]. In the vascular system, increases in ceramide is a contributing factor to renal failure following ischaemia/ reperfusion which is associated with high levels of apoptosis, whereas in coronary arteries ceramide increase stimulated by oxidized LDL results in the proliferation of vascular smooth muscle cells potentiating atherosclerosis, [46,47]. By contrast, the absence of ceramide in specialized areas of the brain like the nigro-striatal neurons is believed to result in the death of these neurons, leading to Parkinson's disease [50,51].…”