Selenopeptide nanomedicine ameliorates atherosclerosis by reducing monocyte adhesions and inflammations

Atherosclerosis is an inflammatory disease that may cause severe heart disease and stroke.Current pharmacotherapy for atherosclerosis shows limited benefits.In the progression of atherosclerosis,monocyte adhesions and inflammatory macrophages play vital roles.However,precise regulations of inflammatory immune microenvironments in pathological tissues remain challenging.Here,we report an atherosclerotic plaque-targeted selenopeptide nanomedicine for inhibiting atherosclerosis progression by reducing monocyte adhesions and inflammation of macrophages.The targeted nanomedicine has 2.2-fold enhancement in atherosclerotic lesion accumulation.The oxidation-responsibility of selenopeptide enables eliminations of reactive oxygen species and specific release of anti-inflammatory drugs,thereby reducing inflammation responses of macrophages.Notably,we find the oxidative metabolite of selenopeptide,octadecyl selenite,can bind to P-selectin in a high affinity with a dissociation constant of 1.5μM.This in situ generated active seleno-species further inhibit monocyte adhesions for anti-inflammation in synergy.With local regulations of monocyte adhesions and inflammations,the selenopeptide nanomedicine achieves 2.6-fold improvement in atherosclerotic plaque inhibition compared with simvastatin in the atherosclerosis mouse model.Meanwhile,the selenopeptide nanomedicine also displays excellent biological safety in both mice and rhesus monkeys.This study provides a safe and effective platform for regulating inflammatory immune microenvironments for inflammatory diseases such as atherosclerosis.

Effects of Wenxiao Ⅱ Decoction on the expression of MCP-1 and VCAM-1 in atherosclerotic rabbits

OBJECTIVE:To observe the effects of different doses of Wenxiao Ⅱ Decoction on the expression of monocyte chemoattractant protein-1(MCP-1) and vascular cell adhesion molecule-1(VCAM-1) in an experimental model of atherosclerosis in rabbits and to explore the mechanism by which it alleviates atherosclerosis.METHODS:Sixty 3-4 month-old New Zealand rabbits of both sexes were randomly divided into six groups:simvastain;model;blank;and high-dose,mid-dose,and low-dose Wenxiao Ⅱ Decoction groups.Except for those in the blank group,all rabbits were fed a high-cholesterol diet.Carotid atherosclerosis was established by balloon-induced injury to the endothelium of the carotid artery in conjunction with consumption of a high-cholesterol diet.After 8 weeks,all rabbits were killed to evaluate the expression of MCP-1 and VCAM-1 by immunohistochemical staining.RESULTS:Expressions of MCP-1 and VCAM-1 were significantly decreased in all groups except the blank group compared with the model group(P<0.05).When compared with the simvastain group only variation of MCP-1 expression in low-dose group was not appreciable,and the differences were indistinct(P<0.05).When comparing among Wenxiao Ⅱ Decoction groups,MCP-1 expression in the mid-and high-dose groups was significantly lower than that seen in the low-dose group(P<0.01),but there were no differences among three dosage groups with respect to VCAM-1 expression(P>0.05).CONCLUSION:These data suggested that high,mid,and low doses of Wenxiao Ⅱ Decoction can inhibit the expression of MCP-1 and VCAM-1,which may prevent the formation of or stabilize atherosclerotic plaques.There may be a direct relationship between the dosage of Wenxiao Ⅱ Decoction and its therapeutic efficacy.