Effect Of Selenium Nanoparticles On Atherosclerotic Lesions And Its Biosafety In Apolipoprotein E-Deficient Mice

Atherosclerotic cardiovascular diseases（CVD）are the leading cause of mortality and a major cause of morbidity and disability worldwide,and has become a serious threat to human health.Therefore,the study for the prevention of atherosclerosis（AS）is urgent.The deficiency of selenium,an essential trace element,have a significantly increased risk of atherosclerostic CVD.The supplement of traditional selenium compounds can inhibit AS,but its application in the prevention of AS was limited due to the safety of dosage.Therefore,it is necessary to investigate the safe and efficient form of Se supplement to promote the application of selenium in the prevention of AS.As a unique form of Se,Se nanoparticles（SeNPs）exhibits higher bioavailability and biological activity,and lower toxicity.Our previous studies showed that bovine serum albumin decorated SeNPs（BSA-SeNPs）and chitosan decorated SeNPs（CS-SeNPs）alleviated atherosclerotic lesion in apolipoprotein E-deficient(ApoE^-/-)mice,but the mechanisms have not been elucidated completely.Besides,the treatment of AS requires long-term administration,but it is still unclear the bioactivity and biosafety of SeNPs with a long-term administration.Furthermore,it is worth investigating whether the anti-atherosclerostic effect of SeNPs could be enhanced by changing the size,especially the surface properties of SeNPs.Therefore,high fat diet（HFD）induced ApoE^-/-mice,the most used animal model of AS,were used in this study to investigate the effects and mechanisms of SeNPs with different surface decorations and sizes on AS lesions,and the long-term biosafety of SeNPs.The main research and results contents are as follows:（1）The effect of CS-SeNPs on the early atherosclerosis,endothelial dysfunction and inflammation in ApoE^-/-mice compared with sodium selenite.CS-SeNPs were prepared by reducing Na₂Se O₃with ascorbic acid in the presence of chitosan using a chemical reduction methord.Oral administration of Na₂Se O₃（40μg Se/kg body weight/day）for 10 weeks significantly reduced atherosclerotic lesions in HFD fed ApoE^-/-mice by inhibiting endothelial dysfunction and inflammatory response.Besides,these results were replicated within in vivo experiments on cultured human endothelial cell line EA.hy926,which provided more insights into the mechanisms of SeNPs against AS.Though CS-SeNPs had a comparable effect to Na₂Se O₃ on the inhibiting atherosclerosis,endothelial dysfunction and inflammation in ApoE^-/-mice,exhibited more efficiency than Na₂Se O₃in vivo.（2）The effects of long-term administration of BSA-SeNPs with different sizes on atherosclerotic lesions and long-term biosafety in ApoE^-/-mice.BSA-SeNPs with different sizes（23.1±4.5 nm,40.4±8.3 nm and 86.8±12.7 nm）were prepared by reducing Na₂Se O₃with glutathione in the presence of BSA using a chemical reduction methord.Long-term administration（24-week）of BSA-SeNPs（50μg Se/kg body weight/day）aggravated atherosclerotic lesions in HFD induced ApoE^-/-mice,revealing a potentialcardiovascular toxicity of BSA-SeNPs after long-term administration.Besides,LTA-BSA-SeNPs aggravated liver and kidney injury.The above adverse effects of BSA-SeNPs were size dependent:BSA-SeNPs with the size of 40.4 nm showed the highest adverse effects among the BSA-SeNPs with three sizes.（3）The effect of lentinan（LET）decorated SeNPs（LET-Tw-SeNPs）on atherosclerotic lesion in ApoE^-/-mice and its mechanism were investigated.All different doses（10,25 and50μg Se/kg body weight/day）of LET-Tw-SeNPs alleviated atherosclerotic lesions in HFD fed ApoE^-/-mice significantly by very abundant mechanisms,including inhibiting endothelial dysfunction,inflammatory response,oxidative stress and hyperlipidaemia.Besides,LET-Tw-SeNPs not only had no adverse effects on the growth of ApoE^-/-mice,but also inhibited HFD-induced liver and kidney injury.It is noteworthy that LET-Tw-SeNPs showed a strong anti-AS activity even at very low dosage（10μg Se/kg body weight/day）,indicating that LET-Tw-SeNPs was a potential anti-atherosclerosis drug with high activity.In conclusion,SeNPs with different surface modifications possess anti-atherosclerosis activity,but long-term oral nutritional dose of BSA-SeNPs has certain toxic effects.Among them,LET-Tw-SeNPs exhibited more significant anti-atherosclerosis activity than CS-SeNPs and BSA-SeNPs at low dose.These results not only provide experimental support for promoting the application of selenium in the prevention and treatment of AS in clinic,but also provide new ideas for the development of nanodrugs for the prevention and treatment of AS,having very important scientific significance and potential application prospects.