Adenovirus-mediated overexpression of sphingomyelin synthases 1 and 2 increases the atherogenic potential in mice

Abstract

Sphingomyelin synthase 1 (SMS1) and SMS2 are two isoforms of SMS, the last enzyme for sphingomyelin (SM) biosynthesis. To evaluate the role of SMS in vivo in terms of plasma lipoprotein metabolism, we generated recombinant adenovirus vectors containing human SMS1 cDNA (AdV-SMS1), SMS2 cDNA (AdV-SMS2), or the reporter LacZ cDNA (AdV-LacZ) as a control. On day 7 after intravenous infusion of 2 3 10 11 particles of both AdV-SMS1 and AdV-SMS2 into mice, liver SMS1 and SMS2 mRNA levels as well as SMS activity were significantly increased (2.5-, 2.7-, 2.1-, and 2.3-fold, respectively; P , 0.001). Lipoprotein analysis indicated that AdV-SMS1 and AdV-SMS2 treatment caused no changes of total SM and cholesterol levels but significantly decreased HDL-SM and HDL-cholesterol (42% and 38%, and 27% and 25%, respectively; P , 0.05). It also significantly increased non-HDL-SM and non-HDLcholesterol levels (50% and 35%, and 64% and 61%, respectively; P , 0.05) compared with AdV-LacZ controls. SDS--PAGE showed a significant increase in apolipoprotein B (apoB; P , 0.01) but no changes in apoA-I levels. Moreover, we found that non-HDL from both AdV-SMS1-and AdV-SMS2-treated mice was significantly aggregated after treatment with a mammalian sphingomyelinase, whereas lipoproteins from control animals did not aggregate. To investigate the mechanism of HDL changes, we measured liver scavenger receptor class B type I (SR-BI) levels by Western blot. We found that AdV-SMS1 and AdV-SMS2 mouse liver homogenates contained 50% and 55% higher SR-BI levels than in controls, whereas no change was observed in hepatic ABCA1 levels. An HDL turnover study revealed an increase of plasma clearance rates for ]HDL in both AdV-SMS1 and AdV-SMS2 mice compared with controls. In conclusion, adenovirus-mediated SMS1 and SMS2 overexpression increased lipoprotein atherogenic potential. Such an effect may contribute to the increased plasma SM levels observed in animal models of atherosclerosis and in human patients with coronary artery disease.-Dong, J., J.

Beyond HDL-cholesterol increase: phospholipid enrichment and shift from HDL3 to HDL2 in alcohol consumers

“…i) HDL-like LpA1 containing SM may be even more effective at effluxing cholesterol from fibroblasts than LpA1 without SM (33). ii) There is evidence from animal experiments that excess SM induces an increase of VLDL-CH and LDL-CH but a decrease of HDL-CH (33,34). This situation is contrary to that found in the alcohol consumers of our study, so a general increase of atherogenic SM is unlikely.…”

Molecular Biology of Atherosclerosis

“…Adenoviral delivery of SMS2 to apoE KO mice increased atherosclerosis but also increased non-HDL-C and decreased HDL-C (1914). Similarly, adenoviral expression of SMS1 and SMS2 increased sphingomyelin content and aggregation of APOB-containing lipoproteins after sphingomyelinase treatment (434).…”

Pharmacological Activation of Peroxisome Proliferator-Activated Receptor {Delta} Increases Sphingomyelin Synthase Activity in THP-1 Macrophage-Derived Foam Cell

“…Interestingly, many studies have been presented to confirm that plasma SM participates in the development of atherosclerosis as an independent risk factor [19]. Overexpression of SM upregulated plasma non-HDL-SM and non-HDLcholesterol levels and decreased plasma HDL-SM and HDL-cholesterol levels, suggesting increased lipoprotein atherogenic potential [10]. Conversely, inhibition of sphingolipid synthesis lowered plasma cholesterol and TG levels through suppression of HMG CoA reductase and fatty acid synthase.…”