Mast cell degranulator compound 48-80 promotes atherosclerotic plaque in apolipoprotein E knockout mice with perivascular common carotid collar placement / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Study of the relationship between mast cells and atherosclerosis is mostly dependent on pathological observation and cytology experiments. To investigate the effects of mast cells degranulation on plaque and their possible mechanisms we used apolipoprotein E knockout mice which had been placed perivascular common carotid collar with mast cells degranulator compound 48-80.</p><p><b>METHODS</b>Forty apolipoprotein E knockout mice were fed a western-type diet and operated on with placement of perivascular right common carotid collar. Four weeks after surgery, the mice were intraperitoneally injected with compound 48-80 (0.5 mg/kg) or D-Hanks every other day for 4 times. The serum lipids and activity of tryptase were measured. Tissue sections were stained with hematoxylin and eosin. Corresponding sections were stained with toluidine blue and immunohistochemically with antibodies against macrophage-specific antigen, alpha-smooth muscle actin, interleukin-1beta and von Willebrand factor. Simultaneously, basic fibroblast growth factor was detected by in situ hybridization and immunofluorescence.</p><p><b>RESULTS</b>No pathological change was observed in common carotid non-collar placement but atherogenesis in common carotid collar placement of both groups. There was a significant increase in plaque area ((5.85+/-0.75) x 10(4) vs (0.86+/-0.28) x 10(4) microm(2), P<0.05), the degree of lumen stenosis ((81+/-15)% vs (41+/-12)%, P<0.05), the activity of tryptase in serum ((0.57+/-0.13) U/L vs (0.36+/-0.10) U/L, P<0.05), and the percentage of degranulated mast cells ((80.6+/-17.8)% vs (13.5+/-4.1)%, P<0.05). The expressions of macrophage-specific antigen, alpha-smooth muscle actin, interleukin-1beta, basic fibroblast growth factor and the density of neovessel in plaque were more in the compound 48-80 group than in the control group.</p><p><b>CONCLUSIONS</b>Perivascular common carotid collar placement can promote atherosclerotic plaque formation in apolipoprotein E knockout mice. Compound 48-80 increases plaque area and the degree of lumen stenosis by the mechanism that compound 48-80 promotes proliferation of smooth muscle cells and aggregation of macrophages. Compound 48-80 promotes angiogenesis in plaque. The mechanism is potentially that compound 48-80 increases the expressions of basic fibroblast growth factor mRNA and protein in plaque. Compound 48-80 enhances the expression of interleukin-1beta in plaque.</p>

Concentration polarization of low density lipoprotein at the distal end of carotid stenosis promotes atherogenesis / 生理学报

To test the hypothesis that concentration polarization of atherogenic lipids may occur in the arterial system and play an important role in localization of atherosclerosis, we simulated and measured in vitro the luminal surface concentration of low density lipoprotein (LDL) in local stenosis at the distal end of carotid artery by number simulation and laser scanning confocal microscopy, then we designed carotid stenosis model to test the role of LDL concentration polarization in atherogenesis. The in vitro experiment showed that the luminal surface LDL concentration was higher than the bulk concentration as predicted by the concentration polarization theory. The relative luminal surface LDL concentration changed with the flow velocity and ratio of stenosis. The wall concentration of LDL was highest in the round tube with 40% stenosis at the same velocity, while the wall concentration of LDL was higher when Re was 250 than Re was 500 at the same extent of narrowness. The animal experiment also revealed that general atherogenic plaques obviously occurred at the distal end of local stenosis where concentration polarized. The results strongly support our hypothesis that concentration polarization of lipoproteins occurs in local stenosis at the distal end of carotid artery, and this in turn promotes the localization of atherosclerosis which develops in the arterial system.

Current Progress in ATP-binding Cassette Transporter Al / 生物化学与生物物理进展

ATP-binding cassette transporter Al (ABCAl) is a kind of membrane intergrate protein and may have multiple and diverse functions. It mediates the cellular efflux of phospholipids and cholesterol to lipid-poor apolipoproteinA- Ⅰ (apoA- Ⅰ ) and plays a significant role in high density lipoprotein (HDL) metabolism. Mutations in human ABCAl cause severe HDL deficiencies characterized by the virtual absence of apoA- Ⅰ and HDL and prevalent atherosclerosis. ABCAl expression is highly regulated and implies a variety of molecular actors. All of the nuclear receptors which involve in regulation of ABCAl expression act via the DR4 element in the ABCAl promoter. cAMP up-regulates ABCAl expression by acting both at the transcriptional and translational level. Cytokines have been shown to exert pleiotropic and antinomic effects on ABCAl transcription, In addition to these, some of enzymes and proteins such as protein kinase A, protein kinase CK2, cathepsin D are involved in the regulation of ABCAl expression. The recent progress in the structure, function and regulation of ABCAl transporter is reviewed.