The Effect Of Estrogen On The Rats With Heart Failure Induced By Myocardial Infarction

The dramatic impact of estrogen on cardiovascular health is apparent from population-based studies, which indicate that premenopausal women have little coronary artery disease compared with men, the ratio is 3:1-10:1, that the incidence of the disease rises markedly after menopausal. The hormone replacement can descend the risk of coronary artery disease to the premenopalusl degree. According to that, people think that estrogen have close relevance with the cardiovascular disease.Objective Based on the the rat model, which was ovariectomized and ligated the left anterior descending branch(LAD), we sought to the effect of estrogen and progesterone on the ventricular remodeling, collagen remodeling, neuronal remodeling, blood lipid, ANP and correlative proteins of Ca²⁺ channel, including RyR2 and FKBP12.6, and studied the mechanisms of estrogen on the rats with congestive heart failure.Methods 300 female SD rats were divided into ovariectomized group and sham-operated group. After two weeks, rats' LAD were ligated in order to occur to congestive heart failure. Rats were randomized to MI+sham-OVX group(myocardial infarction and sham-ovariectomy), OVX+sham-MI gorup(ovariectomy and sham-myocardial infarction),OVX+MI group(ovariectomy and myocardial infarction), lowdose BE₂ group(OVX+MI rats treated with lowdose 17-beta-estradio),highdose BE₂ group(OVX+MI rats treated with highdose 17-beta-estradio) and BE2+P group(OVX+MI rats treated with highdose 17-beta-estradio and progesterone). After six weeks, mortality was counted, hemodynamics was medsured by carotid intubatton, and the weight of body, heart,left ventricle and right ventricle were weighted. Myocardium was observed by staining with H.E. and Sinus Red in a supersaturated picric acid solution and viewed by polarization microscopy. Theses items were compared, which included the area of type 1,111 collagen and ratio of type I /III collagen and collagen volume fraction(CVF). Infarctional area and thickness and myocyte cross sectional area were evaluated by image analysis. Immunohistochemical staining was used to detect the expression of tyrosine hydroxylase in order to evaluate the sympathetic neuronal remodeling. The blood lipid, ANP, CRE and ALT were tested. The proteins of rats' cardiomyocytes were deteced, which included RyR2, phosphorylated RyR2 and FKBP12.6.Results 2 weeks after ovariectomy, the body weight of OVX group was higher than that of sham-operation group(P<0.01). The CHF rats models were established by MI operation for 6 weeks, their mortality was 43.5%, the mortality of OVX+sham-MI group' rats was 5.26%, and there was no remarkable difference between two groups in body weight. The mortality was no obvious difference between 5 groups' rats of MI whether ovariectomy or not and whether estrogen or progesterone was used or not.In the condition of OVX, SBP ,DBP and dp/dtmax were lower in OVX+MI group than in OVX+sham-MI group(P<0.05), but LVEDP and dp/dtmin were higher in OVX+MI group than in OVX+sham-MI group(P<0.01). In the condition of MI, the level of SBP was higher in OVX+MI group than in MI +sham- OVX group(P<0.05), but the levels of DBP, dp/dtmax ,dp/dtmin and LVEDP were no difference between the above two groups(P>0.05). The levels of SBP and LVEDP in highdose BE2 group or lowdose BE2 group were lower than that in OVX+MI group(P<0.05). SBP and DBP were higher in BE2+P group than in OVX+MI group(P<0.01), and the levels of dp/dtmax, dp/dtmui and LVEDP had no remarkable difference between the two groups. The levels of SBP, DBP and LVEDP were higher in BE2+P group than in one of the two BE2 groups(P<0.01). There were no marked discrepancy in HR between the 6groups.TVW/BW. LVW/BW and RVW/BW were higher in OVX+MI group than in OVX+sham-MI group or Ml+sham-OVX group(P<0.05). Compared with OVX+MI group, the TVW/BW, LVW/BW and RVW/BW of highdose or lowdose BE2 group are lower(P<0.05), and the datum were showed in dose-dependent manner. The TVW/BW and LVW/BW of BE2+P group shows an diminution vis - a - vis OVX+MI group's(P<0.05);There were no remarkable difference in TVW/BW and LVW/BW between BE2+P group and the two BE2 groups.There was no distinct difference in infarct size between all the groups(P>0.05). The infarct thickness of all groups were compared: The infarct thickness of OVX+MI group was thicker than that of Ml+sham-OVX group(P<0.05);After the estrogen alone or two combinations of estrogen and progesterone were used, the infarct thickness of the medical groups were thinner than that of OVX+MI group, but there was no striking difference in infarct thickness between the all groups(P>0.05).The comparsion of area of Collagen I and III and ratio of I to III:The items of OVX+MI group were notable thicker than Ml+sham-OVX group's(P<0.01). After the medicine was used, the all items decreased, and BE2+P group was distinct lower than OVX+MI group in the area of Collagen I and ratio of I to III(P<0.01). There were no marked difference in these items between all the medicine groups.The comparison of Collagen Volume Fraction(CVF) and myocyte cross sectional area(MCSA): Compared with OVX+MI group, the CVF and MCSA of Ml+sham-OVX group or OVX+sham-MI group decreased obviously(P<0.05). Estrogen or combination with progesterone could decrease the CVF and MCSA, and there is no remarkable difference between the 3 medicine groups.The comparison of sympathetic neuronal density by mmunohistochemical staining: In infracted border zone, the neuronal density of OVX+MI group was greater than that of Ml+sham-OVX group, and that of the 3 medicine groups was smaller than OVX+MI group's. In non-infarcted zone, the neuronal density ofOVX+MI group was greater than that of Ml+sham-OVX group. Estrogen or combination with progesterone could decrease the neuronal density. Whether in infracted border zone or non-infarcted zone, there was no obvious difference between the three medicine groups.The comparison of ANP: ANP of Ml+sham-OVX group was higher than OVX+MI group's(P<0.01). Whether ovariectomy or not, ANP of OVX+sham-MI group was lower than other MI groups'(P<0.01). Estrogen could increase ANP, but there is no obvious significance in statistics. ANP of BE2+P group was higher than OVX+sham-MI group's(P<0.01), and there was no obvious difference between the three medicine groups.Whether in GTP or in CRE, there is no distinct difference between all the groups.The comparison of blood lipid: It was indistinctive that the effect of MI on TC, TG and LDL-C, but ovariectomy was contrary. These items of MI+OVX group is higher than Ml+sham-OVX group's(P<0.01). Estrogen or progesterone could decrease the levels of TC, TG and LDL-C and increase HDL-C level. HDL-C of Ml+sham-OVX group was lower than MI+OVX group's. There was no obvious difference between the three medicine groups.The comparison of RyR2^ RyR2-P and FKBP12.6: Compared with MI+OVX group, RyR2 and FKBP12.6 of Ml+sham-OVX group or OVX+sham-MI group increased obviously(P<0.05), and RyR2-P decreased(P<0.01). Estrogen could increase RyR2 and FKBP12.6 and decrease RyR2-P. RyR2 and FKBP12.6 of BE2+P group were higher, but RyR2-P was lower than MI+OVX group's. There was no obvious difference between the three medicine groups.Conclusions (1) Estrogen can decrease blood pressure, improve the systolic and diastolic function of rats with heart failure, prevent ventricular hypertrophy and myocardium remodeling, and keep the cardiac structure and function. (2) Estrogen can decrease infarct thickness, prevent collagen remodeling, be prone to occur tocardiac rupture. On the other hand, it can decrease collagen hyperplasia and increase myocardial compliance in non-infarcted zone. (3) Estrogen can decrease sympathetic neuronal density in infracted border zone or non-infarcted zone, improve sympathetic neuronal remodeling, and decrease incidences of malignant arrhythmia and sudden death. (4) Estrogen can increase the level of ANP in the rats of decompensated cardiac insufficiency, which is a protective and compensated mechanism, and not only can alleviate symptom but also can improve ventricular remodeling. (5) Estrogen can decrease the levels of TC,TG and LDL-C, and increase HDL-C level, but it do not obviously damage to liver and kidney function. (6) Estrogen can increase the proteins level of RyR2, FKBP12.6 and phosphorylated RyR2, decrease calcium leak, increase the cardiac systolic function, decrease incidence of arrhythmia, and improve electrical remodeling.