| The incidence of cardiovascular disease is significantly increased in postmenopausal women, due to the hypofunction of ovarian, decreasing levels of estrogen and the dysfunction of endocrine system, which are seriously harmful to human health. Epidemiological researches have demonstrated that premenopausal women have lower risk of cardiovascular disease compared to their male counterparts while in postmenopausal women the risk reaches or even exceeds the occurance rate of men. With the development of thrombolytic therapy and percutaneous coronary intervention, myocardial ischemia reperfusion (MI/R) injury is becoming one of the major problems.Supplementing the physiological concentration of estrogen by hormone replacement therapy (HRT) could not only improve menopause sysptoms, but also protect against cardiovascular diseases. However, there are several strict indications, contraindications and side effects in postmenopausal women by chemical synthetic estrogen, so further research on alternative treatments, such as phytoestrogens, is needed.A soy-derived phytoestrogen, soy isflavones (SI), is a group of biologically active plant substances with a similar chemical structure to17β-estradiol (E2), which has the ability of binding to estrogen receptors (ERs). Soy isoflavones could play an alternative role under lower levels of internal estrogen, including preventing osteoporosis, improving menopausal symptoms and reducing the incidence of breast or endometrial cancer, thereby delaying senescence. However, the effect and the mechanism on myocardial ischemia reperfusion injury in ovarietomized rats are unclear.Objectives:To investigate the effect of soy isoflavones on myocardial ischemia reperfusion injury (MI/R) in ovariectomied rats as well as the potential mechanisms.Methods and results:Female SD rats were underwent bilateral ovariectomy (Ovx) or sham ovariectomy. One week after Ovx, rats were randomly divided into eight groups and began to feed soy-free chow. Rats underwent sham ovariectomy operation (Control group) and ovariectomy (OVS group and OVX group) served as respective control. Other ovariectomy rats were given different doses of SI dissolved in0.5%carboxymethyl cellulose (CMC-Na) by gavage (L-SI group:30mg·kg-1, M-SI group:90mg·kg-1, H-SI group:270mg·kg-1). Additional Ovx rats received the same volume of CMC-Na by gavage (CMC group) or50μg·kg-1of17β-estradiol (E2) by subcutaneous injection (OVE group) instead of drug once daily over the same period. After4-week treatments, they were exposed to30minutes of left coronary artery occlusion followed by6or24hours of reperfusion. Compared with CMC group, body weight of SI (270mgkg-1) treated rats was decreased, whilst uterus weight and endogenous estradiol level increased significantly. The infarct area/risk area of SI (90,270mg·kg-1) treated rats was reduced using Evans blue-triphenyltetrazolium chloride (TTC) staining, while cardiac function was improved in SI (90,270mg·kg-1) and E2treated rats. Serum creatine kinase (CK) and plasma malonaldehyde (MDA) declined after treated with SI, however plasma NO level raised. To elucidate the mechanisms of soy isoflavones in myocardial I/R, we found following treatment with SI (90,270mg·kg-1) and E2, subunit of PI3K p85a, serine473phosphorylation of Akt, serine1177phosphorylation of eNOS, IκBα and Bcl-2increased in myocardium, whilst expression of inducible NO synthase (iNOS) and Bax decreased by western blot. Superoxide generation in myocardium was reduced in SI (90,270mg·kg-1) and E2treated rats, measured by the O2--sensitive fluorescent dye Dihydroethidium (DHE). Endothelium-dependent relaxation in aortic rings from SI (90,270mg·kg-1) treated rats was obviously improved in comparison with vehicle-treated rats. Compared with CMC, SI (90,270mg·kg-1) activated the p85α and phosphorylation of Akt ser473residue, increased IκBα and decreased iNOS in aorta by western blot. Besides the production of O2-generation was lessened after treated with SI (90,270mg·kg-1) and E2in aorta, as measured by DHE.Conclusions:These results indicate that soy isoflavones could activate PI3K/Akt/eNOS signaling pathway, inhibit the oxidative stress and reduce myocardium apoptosis, therefore protect myocardium from MI/R injury in ovariectomied rats. Simultaneously, soy isoflavones improves the endothelial function by decreasing oxidative stress and activating PI3K-Akt. In brief, all these results provide a solid reaserch basis for the wildly use and potential applications of soy isoflavones in the treatment of postmenopausal MI/R injury and other cardiovascular diseases. |
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