Vascular Protective Effects And Mechanism Research Of PQS On Postmenopausal Women With Coronary Heart Disease

Epidemiological studies have shown that there is gender difference in the incidence of cardiovascular disease. The incidence of cardiovascular disease is lower in premenopausal women compared to men, however, there is no difference between postmenopausal women and men. These suggest that endogenous estrogen may have vascular protective effects. As a result, estrogen replacement therapy (ERT)have been a research hotspot in the medicine field. Unfortunately, several clinical studies documented that ERT could increase the incidence of cardiovascular disease in postmenopausal women while protecting vascular endothelial cell. And ERT may lead to serious side-effects, such as invasive breast cancer, endometrial cancer, deep vein thrombosis. Therefore the physicians conceive whether there is an estrogen-like substance with no or little adverse reaction of estrogen. Researchers actively begin to seek and study estrogen-like medicine.Our previous studies have shown that PQS has vascular protective effects. It can prevent vascular endothelial cell from superoxidation damage and oppose atherosclerosis. American ginseng can tonify the archaeus in TCM. Archaeus is parallel to estrogen in some aspects. As a result, we speculate that PQS may have estrogen-like effects. In our study, we firstly observed the influence of PQS on postmenopausal women with coronary heart disease from the level of serum estradiol, lipid metabolism, oxidative stress, inflammatory response and vascular endothelial function. And the model of ovariectomy ApoE-/-female mice with atherosclerosis was made to observe the influence of PQS on serum estradiol, estrogenic effects and the key protein of estrogen receptor-mediated PI3K/Akt signal transduction pathway. Above all, clinical study and animal experimental research were conducted to determine whether PQS has estrogen-like vascular protective effects and to provide the foundation for PQS to prevent and treat coronary heart disease.This study is divided into three parts:literature review, clinical study and animal experimental research.1Literature Review:In this part, there are two reviews. One is the research advancement on cardiovascular protective effects of phytoestrogen, the other is estrogen receptor-mediated signal transduction pathway and cardiovascular system.2Clinical research:Study on vascular protective effects of xin yue capsule on postmenopausal women with coronary heart disease.Objective:To observe vascular protective effects of xin yue capsule on postmenopausal women with coronary heart disease.Methods:All cases were randomly divided into postmenopausal CHD female patients with xin yue capsule plus conventional western medicine for12weeks(experimental group, n=40subjects), postmenopausal CHD female patientswith only conventional western medicine(control group, n=40subjects) and the healthy control(n=30subjects). CHD patients were diagnosed according to the1999ACC/AHA/ACP-ASIM Guidelines for the Management of Patients with Chronic Stable Angina and the2002ACC/AHA Guidelines for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction. A diameter stenosis of at least50%was diagnosed by visible estimation in a major coronary artery from standard selective coronary angiography. Postmenopausal period is judged according to the1999International Menopause Society definition. The level of serum estradiol was determined in blood samples taken following fasting from postmenopausal CHD female patients with xin yue capsule plus conventional western medicine, postmenopausal CHD female patients with only conventional western medicine and the healthy group by electrochemiluminescence immunoassay; the levels of serum NF-κB, sICAM-1, sE-selectin, NO and ET-1in three groups were determined by ELISA; SOD and MDA of three groups were determined by biochemical technique.Results:In comparison with healthy group, the levels of serum estradiol, SOD activity, NO and HDL-C in CHD group were all significantly decreased, the levels of serumTC, TG, LDL-C, MDA, NF-κB, sICAM-1, sE-selectin, and ET-1were all significantly increased(P<0.01or P<0.05). In comparison with control group, serum estradiol, SOD activity, NO and HDL-C had an upward trend in experimental group, and serum TC, TG, LDL-C, MDA, NF-κB, sICAM-1, sE-selectin and ET-1had an downward trend in experimental group (P>0.05)Conclusion:The levels of estradiol decreased significantly in the postmenopausal women with coronary heart disease. Xin yue capsule can increase the estradiol in the experimental group. It can play a role in protecting the vessel not only by ameliorating fat metabolism disorder but also by opposing oxidative stress, inhibiting the inflammatory reaction and regulating vasomotor state.3Animal experimental research:Vascular protective effects and mechanism research of PQS on ovariectomy ApoE-/-female mice with atherosclerosis(AS).Objective:To observe vascular protective effects and the corresponding mechanisms of PQS on ovariectomy ApoE-/-female mice with atherosclerosis(AS).Methods:The ovariectomy model of atherosclerosis were established by removing their ovaries of ApoE-/-mice plus high fat and high caloric laboratory chow for12w. The successful models were divided into five groups:model group, estradiol group(E2), panax quinquefolius saponin group(PQS), estradiol plus estrogen receptor antagonist (fulvestrant) group(EA), PQS plus estrogen receptor antagonist group(PQSA). C57BL/6J put on the normal diet for12w were selected as the control group. The mice in each group were drenched the corresponding medicine or distilled water. The mice in EA and PQSA group were intramuscular injection fulvestrant once a month. Twelve weeks later, the aortic arteries technology observation of morphological change, biochemical assay of superoxide dismutase (SOD) and malondialdedyde (MDA), ELISA assay of estradiol, NO, ET-1, NF-κB, E-selectin, ICAM-1, RT-PCR of iNOS and eNOS. p-Akt expression by western-blot.Results:①Aortic atherosclerotic plaque in model group contains a lot of lipids, macrophages and vascular smooth muscle cells, whereas collagen compositon was reduced. Similar to E2, PQS can ameliorate atherosclerosis.②In comparison with control group, the levels of serum estradiol and SOD were all significantly decreased in model group, MDA, NF-κB, E-selectin, ICAM-1, NO, ET-1were all significantly increased (P<0.01or P<0.05); In comparison with model group, the levels of serum estradiol and SOD were all significantly increased in E2 and PQS group, MDA, NF-κB, E-selectin, ICAM-1, NO, ET-1were all significantly decreased(P<0.01or P<0.05); Although the level of estradiol was higher than model group, the levels of each index were not statistically significant in EA group (p>0.05). The results of PQS A group were similar to EA group.③RT-PCR results showed the gene expression of iNOS of model group in aorta was significantly higher than control group and the gene expression of eNOS was lower than control group (P<0.01); In comparison with model group, the gene expression of iNOS in E2and PQS group decreased significantly, the gene expression of eNOS increased significantly(P<0.01); but the levels of iNOSmRNA and eNOSmRNA were not statistically significant in EA and PQSA group(P>0.05).④Western-blot results showed that p-Akt of model group was significantly less than control group (P<0.01); compared with model group, p-Akt of E2and PQS group had a further increase(P<0.01), but the level of p-Akt was not statistically significant in EA and PQSA group(P>0.05).Conclusion:The level of estrogen drop obviously in ovariectomy ApoE-/-female mice with atherosclerosis accompanied with lipid metabolism disorder and high levels of inflammatory markers. Our research show that PQS has the ability to raise the level of serum estradiol, improve lipid metabolism disorder, reduce oxidative stress reaction, inhibit inflammatory reaction and promote Akt protein phosphorylation. These effects can be blocked by ER antagonist. The protective actions of PQS are essentially mediated by a combination of estrogen and its receptor.