Increase in Secretory Sphingomyelinase Activity and Specific Ceramides in the Aorta of Apolipoprotein E Knockout Mice during Aging

Abstract

Atherosclerosis is caused by many factors, one of which is oxidative stress. We recently demonstrated that systemic oxidative stress increased secretory sphingomyelinase (sSMase) activity and generated ceramides in the plasma of diabetic rats. In addition, we also showed that the total ceramide level in human plasma correlated with the level of oxidized low-density lipoprotein. To investigate the relationship between ceramide species and atherogenesis during aging, we compared age-related changes in ceramide metabolism in apolipoprotein E knock out mice (apoE −/− ) and wild type mice (WT). Although the total plasma ceramide level was higher in apoE −/− than that in WT at all ages, it decreased with increasing age. sSMase activity increased at 65 weeks (w) of age in both strains of mice. When apoE −/− developed atherosclerosis at 15 w of age, C18:0, C22:0, and C24:0 ceramide levels in the apoE −/− aorta significantly increased. Furthermore, at 65 w of age C16:0 and C24:1 ceramide levels were significantly higher than those in WT. These results suggested that elevation in levels of specific ceramide species due to sSMase activity contributed to atherogenesis during aging.

Top-down lipidomics of low density lipoprotein reveal altered lipid profiles in advanced chronic kidney disease

“…Hu et al ( 17 ) reported that STs were the only factor that discriminated control from ESRF groups in their study, and that they have promise as biomarkers for CKD. We observed a decrease in the level of Cer's in LDL from CKD patients; however, as increased sphingomyelinase activity and free Cer's are thought to be linked to atherogenesis ( 48,49 ), this does not appear to contribute to the proatherogenic profi le of CKD. Finally, it was also noted that there was a signifi cant increase in N-acyltaurines (NATs) in LDL from CKD patients.…”

Secretory sphingomyelinase in health and disease

“…While neutral sphingomyelinase levels are unchanged in the liver and kidney, plasma S-ASM activity increases. These findings suggest that the induction of diabetes increases plasma ceramide levels by enhancing S-ASM activity (Kobayashi et al, 2013).…”

“…Irradiation induces increases in S-ASM activity in some but not all tumor patients, and a positive correlation between S-ASM activity and serum ceramide concentration has been observed (Sathishkumar et al, 2005). In rodents, increasing age is associated with increased S-ASM activity and a simultaneous increase in the concentration of individual ceramide species (Kobayashi et al, 2013). Other in vivo studies did not report the expected relationship between S-ASM activity and sphingolipid concentrations.…”

“…At 65 weeks of age, C16:0 and C24:1 species are increased compared to WT mice. These findings indicate that an age-related increase in S-ASM activity, which results in an elevation of certain ceramide species, may contribute to age-related atherosclerosis (Kobayashi et al, 2013). When ApoE -/-mice are treated with a recombinant adeno-associated virus (AAV) that constitutively expresses high levels of human ASM in the liver and plasma, S-ASM levels are persistently elevated.…”

Demographic and clinical variables affecting mid‐ to late‐life trajectories of plasma ceramide and dihydroceramide species

“…However, we previously found that levels of CSF very long chain ceramides with chain lengths of C20–C26 were higher in APOE E4 carriers compared with noncarriers (Mielke et al ., 2014). Further, studies of Alzheimer (Bandaru et al ., 2009) and HIV dementia brains (Cutler et al ., 2004) and aortic tissue levels of APOE knockout mice (Kobayashi et al ., 2013) have found APOE genotype alters ceramide levels in these compartments. Thus, the relationship between ceramides and APOE genotype likely varies depending on the compartment and disease state.…”