| Background and Aims:Atherosclerosis (AS) is one of the serious diseases that threaten the health of human being. Traditionally, high serum total cholesterol (TCL) is the major factor for AS. However, recent clinical epidemiological study have revealed that the TCL level is among the normal range for about 50 percent of AS patient, indicating that other etiological factors maybe contribute to AS. In addition, some inflammation diseases such as chronic bronchitis, prostatitis and gingivitis are positive related to high AS morbility. And the content of monocyte chemoattractant protein-1 (MCP-1) and C-reactive protein (CRP) increased in the patients with cardiovascular diseases. Taken together, inflammation and immunological factors play very important roles in the progress of AS.In Chinese Medicine, AS is the stagnated blood disease and promoting blood flow is the effective therapy. Panax notoginseng saponins (PNS) is the principal ingredient extracted from the traditional Chinese herb medicinal P. notoginseng and has extensive effects on the cardiovascular system, such as inhibiting platelet aggregation, increasing the blood flow of the coronary arteries, improving left ventricular diastolic function in hypertension patients, protecting the damage resulted from myocardial ischemia, showing an obvious anti-inflammatory effect due to reduction of the level of the intracellular free calcium concentration in neutrophils, reducing the myocardial oxygen consumption, and anti-arrhythmia, etc. Our previous experiments indicated that inflammation stimulation could induce the formation of foam cells, which can be inhibited through the anti-inflammation action of PNS.To investigate the mechanism of therapeutic action of PNS on AS, AS model of rats was employed in our study. Differential gene expression analysis by gene chip is the major method to study mechanism of Chinese medicine. The key molecules for the progress of AS were determined in this study, which provide a solid evidence for further applied study.Methods:1. Thirty rats were divided in to three groups randomly, i.e. Control (injected with sterilitas liquid paraffin, ip), Zym group (injected with Zymosan,20mg/kg,once every 3 days) and PNS group (treated with Zym ip +PNS 100mg/kg, once daily). All the animals were fed with high fat diet containing 3% cholesterol for 9 weeks.2. Serum TCL level and TGL were measured by enzymatic method and tissue slides were observed under electron microscopy.3. Three experiment groups: a, control, sterilitas liquid paraffin, ip; b, model, Zym,20mg/kg,one time every 3 days; c, treatment group, one time every 3 days +PNS (100mg/kg, once a day), The animals in Zym group and treatment group were fed with high fat diet containing 3% cholesterol for 9 weeks. The profiles of gene expression were determined by functional gene chip and were confirmed by real-time PCR and western blot.4. Macrophages were harvested from abdominal cavity of rats by stimulating with 1640 medium and cultured in vitro with LPS. Base on LPS, macrophages were treated with PNS (10, 30 or 100μg/ml, respectively). P397 FAK phosphorylation level in macrophages was detected by western blotting technique.Results:1. Endothelial cells in Zym group were damaged seriously, desquamated from artery walls and covered by adjacent endothelial cells. Swellened cytoplasm, phagotrophic lipid droplets and twisted nuclei presented in the endotheliocytes. Subendothelial space widened and subintimal smooth muscle cells permeated through elastic plank. After treated with PNS, the damage of endotheliocytes and smooth muscle cells relieved significantly.2. PNS obviously decreased the expression of MMP2, MMP9, MMP7, IL-18, IL-1b, Edn and TF, which are increased in the Zym group by comparison of control group. However, the expression of ANF and iNOS increased after treatment with PNS. The expressions of integrin family members increased markedly in Zym group and were reduced by PNS.3. The western blots showed that the expression of NFκB increased and IκBαdecreased significantly in Zym group, whereas PNS inhibited these changes obviously.4. Activated FAK was mainly expressed in the cytoplasm of macrophages. PNS could inhibit the phosphorylation of P397 FAK induced by LPS in macrophages significantly.Conclusion:1. PNS can markedly decrease the serum lipid level, improve the function of endothelial cells and inhibit the expression of endothelin 1, 2, 3 and coagulation factor III.2. PNS down-regulate inflammation-related genes, especially adhesion molecules, such as integrin. And PNS inhibit the expression of NFκB and its activity. In addition, PNS up-regulate IκB expression and directly inhibit FAK activation.3. PNS significantly increases the expression of iNOS and ANF. iNOS and ANF can obviously relax blood vessels, which is consistent with the traditional function of PNS.4. The effects of PNS on atherosclerosis are related with its anti-inflammatory and lipidemic-modulating actions. |
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