Acid sphingomyelinase promotes lipoprotein retention within early atheromata and accelerates lesion progression

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. Methods and Results - We studied atherogenesis and lipoprotein retention in Asm^-/- versus Asm ^+/+ mice on the Apoe^-/- and Ldlr^-/- backgrounds. Asm^-/-; Apoe^-/- mice had a ≈40% to 50% decrease in early foam cell aortic root lesion area compared with Asm ^+/+;Apoe^-/- mice (P<0.05) despite no difference in plasma cholesterol or lipoproteins. To assay lipoprotein retention in vivo, the two groups of mice were injected with fluorescently labeled Apoe^-/- lipoproteins. Early foam cell lesions of Asm^-/-; Apoe^-/- mice showed a striking 87% reduction in lipoprotein trapping (P<0.0001) compared with Asm^+/+;Apoe^-/- lesions. Similar results were obtained with Ldlr^-/- mice, including an 81% reduction in lipoprotein retention within Asm^-/-;Ldlr^-/- lesions compared with Asm^+/+;Ldlr^-/- lesions (P<0.0005). Conclusions - These findings support a causal role for acid SMase in lipoprotein retention and lesion progression and provides further support for the response-to-retention model of atherogenesis.