hirudin and Atherosclerosis

Atherosclerosis is a leading cause of death globally. Targeted imaging and therapeutics are desirable for the detection and treatment of the disease. In this study, we developed trifunctional Simian virus 40 (SV40)-based nanoparticles for in vivo targeting and imaging of atherosclerotic plaques. These novel trifunctional SV40-based nanoparticles encapsulate near-infrared quantum dots and bear a targeting element and a drug component. Using trifunctional SV40-based nanoparticles, we were able to noninvasively fluorescently image atherosclerotic plaques in live intact ApoE(-/-) mice. Near-infrared quantum dots encapsulated in the SV40 virus-like particles showed prominent optical properties for in vivo imaging. When different targeting peptides for vascular cell adhesion molecule-1, macrophages, and fibrin were used, early, developmental, and late stages of atherosclerosis could be targeted and imaged in live intact ApoE(-/-) mice, respectively. Targeted SV40 virus-like particles also delivered an increased concentration of the anticoagulant drug Hirulog to atherosclerosis plaques. Our study provides novel SV40-based nanoparticles with multivalency and multifunctionality suitable for in vivo imaging, molecular targeting, and drug delivery in atherosclerosis.

Topics: Animals; Atherosclerosis; Drug Delivery Systems; Hirudins; Mice; Mice, Knockout, ApoE; Nanoparticles; Peptide Fragments; Plaque, Atherosclerotic; Quantum Dots; Recombinant Proteins; Simian virus 40

To explore the effect and mechanism of hirudin on atherosclerotic plaques in apolipoprotein E knockout (ApoE(-/-)) mice.. Totally 24 ApoE(-/-) mice, 7-8 weeks old were fed with high fat diets. They were randomly divided into the recombinant hirudin treatment group (drug group) and the model group according to body weight and different dens, 12 in each group. Twelve C57BL/6J mice, 7-8 weeks old fed with high fat diet were recruited as the normal control group. Recombinant hirudin (0.25 mg/kg) was intraperitoneally injected to mice in the drug group from the 10th week old once every other day for five successive weeks. Equal volume of normal saline was injected to mice in the model group. Mice in the normal control group received no treatment. All mice were sacrificed after fed with high fat diet until they were 20 weeks old. Serum levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), high-sensitive C-reactive protein (hs-CRP), E-selectin, interleukin-6 (IL-6), and stromal metalloproteinase-2 (MMP-2) were detected. The plaque/lumen area and extracellular lipid composition/ plaque area were analyzed by HE staining and morphometry. Changes of signaling molecules in store-operated calcium channels, including stromal interacting molecule 1 (STIM1), Orail protein, and transient receptor potential channel 1 (TRPC1) were determined by Western blot. Results Lipid plaque formed in the aorta vessel wall of 20-week old mice in the model group. Compared with the normal control group, serum levels of TC, TG and LDL increased (P<0.01), hs-CRP, E-selction, IL-6, and MMP-2 obviously increased (P<0.01, P<0.05) in the model group; expression levels of STIM1, TRPC1, and Orail significantly increased (P<0.01). Compared with the model group, the plaque/lumen area and the extracellular lipid composition/plaque area significantly decreased in the drug group (P<0.05, P<0.01); serum levels of TC and LDL, hs-CRP, E-selction, IL-6, and MMP-2 obviously decreased (P<0.05, P<0.01); expression levels of STIM1, TRPC1, and Orail were significantly down-regulated (P<0.05, P<0.01).. Hirudin could significantly improve lipids and endothelial functions of ApoE(-/-) mice, down-regulate expression levels of STIM1, Orai1, and TRPC1, and thus delaying the occurrence and development of atherosclerosis.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; C-Reactive Protein; Cholesterol; Diet, High-Fat; Drugs, Chinese Herbal; E-Selectin; Hirudins; Interleukin-6; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Mice; Mice, Inbred C57BL; Mice, Knockout; Plaque, Atherosclerotic; Recombinant Proteins; Triglycerides