Acid Sphingomyelinase Promotes Lipoprotein Retention Within Early Atheromata and Accelerates Lesion Progression

Abstract

Objective-The key initial step in atherogenesis is the subendothelial retention of apolipoprotein B-containing lipoproteins. Acid sphingomyelinase (acid SMase), an enzyme present extracellularly within the arterial wall, strongly enhances lipoprotein retention in model systems in vitro, and retained lipoproteins in human plaques are enriched in ceramide, a product of SMase. We now sought to test a direct causative role for acid SMase in lipoprotein retention and atherogenesis in vivo. T he key initial step in early atherogenesis is the retention, or trapping, of apoB-lipoproteins within the subendothelium of focal susceptible regions of the arterial tree. [1][2][3] Retained and modified lipoproteins provoke a series of biological responses that can explain all subsequent features of early atherogenesis. 1,2 Lipoprotein retention within prelesional segments initially involves direct binding of positively charged domains on apoB to negatively charged elements of arterial matrix, chiefly proteoglycans. 4,5 In later stages, lipoprotein retention can be enhanced further by size-related trapping of large lipoproteins in the subendothelium and by uptake by subendothelial macrophages (below). Moreover, lesional cells secrete additional molecules, such as sphingomyelinase and lipoprotein lipase, that are proposed to shift the molecular basis for further lipoprotein retention while also substantially accelerating retention and hence lesion progression. Thus, understanding the molecular mechanisms of subendothelial lipoprotein retention in prelesional and then lesional arteries is a critical goal of atherogenesis research.Previous work has suggested a number of factors that can influence subendothelial lipoprotein retention, including (1) the concentration of circulating atherogenic lipoproteins; (2) endothelial permeability; (3) the nature and amounts of proretentive molecules within the subendothelial space, notably proteoglycans and lipoprotein lipase (LpL), which bridges lipoproteins to matrix; and (4) structure and composition of the lipoproteins, which can be altered by enzymatic and nonenzymatic processes within the subendothelial space. [1][2][3] A large number of studies in vitro implicate the secretory form of acid sphingomyelinase (S-SMase) in proretentive modifications of atherogenic lipoproteins. S-SMase arises from the acid SMase (Asm) gene, which also gives rise to lysosomal acid SMase. 6 S-SMase is secreted by cell types Correlative support for a role of S-SMase in atherogenesis per se has been provided by several human and animal atherosclerosis studies. For example, extracellular acid SMase is present in human and murine atherosclerotic lesions, 16 and aggregated lipoproteins extracted from human atheromata are specifically enriched in ceramide, indicating hydrolysis by sphingomyelinase. 12 Moreover, recent work has demonstrated an association between high SM content in circulating lipoproteins, which enhances S-SMase-mediated hydrolysis, and increased risk for aortic atherosclerosis in mice and coronary...

Conformational changes of apoB-100 in SMase-modified LDL mediate formation of large aggregates at acidic pH

“…In this work, lipoprotein lipase was found to play a purely structural role in linking aggregated LDL to the matrix. Interestingly, arterial-wall matrix, lipoprotein lipase, and SMase have each been shown to contribute to retention of apoB-100-containing lipoproteins and atherogenesis in vivo ( 6,(42)(43)(44).…”

Molecular Biology of Atherosclerosis

“…Secreted ASM cleaves sphingomyelin to ceramide, promotes lipoprotein binding and retention, and greatly increases uptake and foam cell formation for a number of lipoproteins (417).…”

Sphingomyelin Phosphodiesterase Acid-like 3A (SMPDL3A) Is a Novel Nucleotide Phosphodiesterase Regulated by Cholesterol in Human Macrophages

“…aSMase is capable of hydrolyzing sphingomyelin in oxidized LDL particles, transforming them into a more aggregation-prone form that is more readily retained by arterial proteoglycans (4,5). The activity of aSMase appears pro-atherogenic in vivo, where it promotes the retention of lipoprotein in the subendothelium and contributes to the growth of atherosclerotic plaques in the aortae of mice (6).…”