Adeno‐associated virus‐mediated expression of acid sphingomyelinase decreases atherosclerotic lesion formation in apolipoprotein E^−/− mice

Abstract

Unexpectedly, the lesion area of the entire aorta was reduced significantly in the AAV8-ASM virus-treated group. Hepatic expression and secretion of ASM into the circulation did not accelerate or exacerbate, but rather decreased, lesion formation in ApoE(-/-) mice. Thus, plasma ASM activity does not appear to be rate limiting for plaque formation during atherogenesis.

Secretory sphingomyelinase in health and disease

“…Plaque formation in the aortic sinus after 17 weeks did not differ in mice treated with a control AAV. These findings suggest that S-ASM has no accelerating or exacerbating role in atherosclerotic lesion formation in the ApoE -/-model of atherosclerosis (Leger et al, 2011).…”

“…Feeding rats grape seed oil vs. butter leads to increased S-ASM activity and, simultaneously, decreased ceramide concentrations (Drachmann et al, 2007). The induction of S-ASM activity by adeno-associated virus in ApoE -/-mice resulted in only minor changes in SM and ceramide: a small reduction of SM and ceramide in plasma at several time points after injection and a reduction of SM and unaltered ceramide concentrations in the liver (Leger et al, 2011). Correlations between S-ASM in plasma SM and ceramide were previously reported only sporadically (Sathishkumar et al, 2005).…”

Rutaecarpine suppresses atherosclerosis in ApoE−/− mice through upregulating ABCA1 and SR-BI within RCT

“…For en face analysis, aortas were split longitudinally ( 27 ). Sections and fi xed aortas were stained with Oil Red O (ORO) for 30 min and rinsed ( 28 ). Images of the ORO staining sections and the open luminal surface of the vessels were captured with a Leica Q550cw Graphic Analysis System and a digital camera (Sony), respectively.…”

Control of autophagy maturation by acid sphingomyelinase in mouse coronary arterial smooth muscle cells: protective role in atherosclerosis

“…The pooling of ASM in secretory lysosomes seems to participate in signal transduction events; however, the precise role of ASM in the development of atherosclerosis remains unclear. Secretory ASM may be atherogenic, whereas the lysosomal form of ASM may have anti-atherogenic effects[2-5]. Previous studies demonstrated that the atherogenic action of secretory ASM in the plasma may be mainly associated with ceramide-promoted lipoprotein aggregation or uptake by arterial-wall macrophages that leads to foam cell formation[5-6].…”

“…Previous studies demonstrated that the atherogenic action of secretory ASM in the plasma may be mainly associated with ceramide-promoted lipoprotein aggregation or uptake by arterial-wall macrophages that leads to foam cell formation[5-6]. However, a recent study demonstrated that adenovirus-mediated expression and secretion of ASM into the circulation did not exacerbate but decreased lesion formation in atherosclerotic ApoE −/− mice, indicating that plasma ASM activity may not be determinant for plaque formation during atherogenesis[2]. In another aspect, lysosomal ASM activity can be anti-atherogenic since it increases sphingomyelin hydrolysis reducing accumulation of cholesterol in lysosome of macrophages given that sphingomyelin has high binding affinity to cholesterol[7-8].…”