Intervention effects of estradiol on myocardial ischemia- reperfusion injury of rat and its mechanisms

doi:10.12047/j.cjap.6362.2022.116

Abstract

Abstract: Objective: To study the effects of estradiol (E2) on alleviating myocardial ischemia/reperfusion(I/R) injury through estrogen receptorβ(ERβ) mediated extracellular regulated protein kinases(ERK) pathway activation. Methods: Eighty-four adult female SD rats were ovariectomized and randomly divided into control group, NC siRNA adeno-associated virus (AAV) group received sham operation, the myocardial I/R injury model was prepared by ligation of the left anterior descending coronary artery in I/R group, E2+I/R group, NC siRNA AAV+I/R group, NC siRNA AAV+E2+I/R group and ERβ-siRNA AAV+E2+I/R group. E2+I/R group, NC siRNA AAV+E2+I/R group and ERβ-siRNA AAV+E2+I/R group were treated with E2 0.8 mg/kg by gavage for 60 days before modeling. NC siRNA AAV+I/R group, NC siRNA AAV+E2+I/R group, and ERβ-siRNA AAV+E2+I/R group were treated with AAV by caudal vein injection 24 h before modeling. After 120 min of reperfusion, the contents of serum lactate dehydrogenase (LDH), phosphocreatine kinase (CK), phosphocreatine kinase isoenzyme (CK-MB), myocardial infarction area and the expressions of ERβ, p-ERK, the contents of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1 β), malondialdehyde (MDA) and total antioxidant capacity (T-AOC) in myocardium were measured. Results: The contents of serum LDH, CK, CK-MB, myocardial infarction area and the contents of TNF-α, IL-1 β, MDA in myocardium of I/R group were higher than those of the control group, the expression levels of ERβ and p-ERK and the content of T-AOC were lower than those in the control group (P＜0.05). The contents of serum LDH, CK and CK-MB, myocardial infarction area and the contents of TNF-α, IL-1 β and MDA in myocardium of E2+I/R group were lower than those of the I/R group, the expression levels of ERβ and p-ERK and the content of T-AOC were higher than those of the I/R group(P＜0.05). After knockdown ERβ by caudal vein injection of ERβ-siRNA AAV, the contents of serum LDH, CK and CK-MB, myocardial infarction area and the contents of TNF-α, IL-1 β and MDA in myocardium of ERβ-siRNA AAV+E2+I/R group were higher than those of NC-siRNA AAV+E2+I/R, the expression levels of ERβ and p-ERK and the content of T-AOC were lower than those of NC-siRNA AAV+E2+I/R(P＜0.05). Conclusion: E2 has protective effects on myocardial I / R injury in ovariectomized rats, which are related to the promotion of ERβ mediating the activation of ERK pathway, reducing inflammatory and oxidative stress responses.

Key words: myocardial ischemia/reperfusion, estradiol, estrogen receptor β, extracellular regulated protein kinase, inflammatory response, oxidative stress response, rats

CLC Number:

R542

FENG Jing-ru, ZHANG Hai-yang, SHI He, WANG Teng-fei, WANG Zi-jian, CHENG Guang-hui, BI Sheng-li. Intervention effects of estradiol on myocardial ischemia- reperfusion injury of rat and its mechanisms[J]. CJAP, 2022, 38(6): 638-643.

References

[1] Freaney PM, Khan SS, Lloyd-Jones DM, et al. The role of sex-specific risk factors in the risk assessment of atherosclerotic cardiovascular disease for primary prevention in women[J]. Curr Atheroscler Rep, 2020, 22(9): 46.
[2] Zhu D, Chung HF, Dobson AJ, et al. Type of menopause, age of menopause and variations in the risk of incident cardiovascular disease: pooled analysis of individual data from 10 international studies[J]. Hum Reprod, 2020, 35(8): 1933-1943.
[3] Kumar A, Boovarahan SR, Prem PN, et al. Evaluating the effects of carbon monoxide releasing molecule-2 against myocardial ischemia-reperfusion injury in ovariectomized female rats[J]. Naunyn Schmiedebergs Arch Pharmacol, 2021, 394(10): 2103-2115.
[4] 钱鲁, 李卓远, 张素勤. 雌二醇对小鼠急性心肌缺血再灌注损伤的保护作用及其机制[J]. 温州医科大学学报, 2021, 51(7): 548-553.
[5] 张梦颖, 杨玉有, 刘敏, 等. 雌二醇通过 ERβ调控 ERK 磷酸化影响细胞增殖和凋亡[J]. 南方医科大学学报, 2021, 41(3): 336-343.
[6] 骆燕萍, 俞艳烨, 邹茜. 绝经前后冠心病患者临床特点雌激素及冠状动脉病变特征分析[J]. 中国妇幼保健, 2021, 36(20): 4846-4848.
[7] Wang A, Gerstein HC, Lee SF, et al. Testosterone and sex hormone-binding globulin in dysglycemic women at high cardiovascular risk: A report from the outcome reduction with an initial glargine intervention trial[J]. Diab Vasc Dis Res, 2021, 18(2): 14791641211002475.
[8] Yang Y, Wang IW, Turrentine M, et al. Postischemic application of estrogen ameliorates myocardial damage in an in vivo mouse model[J]. J Surg Res, 2018, 231: 366-372.
[9] Wang M, Smith K, Yu Q, et al. Mitochondrial connexin 43 in sex-dependent myocardial responses and estrogen-mediated cardiac protection following acute ischemia/reperfusion injury[J]. Basic Res Cardiol, 2019, 115(1): 1.
[10] da Silva JS, Montagnoli TL, Rocha BS, et al. Estrogen receptors: Therapeutic perspectives for the treatment of cardiac dysfunction after myocardial infarction[J]. Int J Mol Sci, 2021, 22(2): 525.
[11] Zhai P, Eurell TE, Cooke PS, et al. Myocardial ischemia-reperfusion injury in estrogen receptor-alpha knockout and wild-type mice[J]. Am J Physiol Heart Circ Physiol, 2000, 278(5): H1640-7.
[12] Bozdogan O, Bozcaarmutlu A, Kaya ST, et al. Decreasing myocardial estrogen receptors and antioxidant activity may be responsible for increasing ischemia- and reperfusion-induced ventricular arrhythmia in older female rats[J]. Life Sci, 2021, 15(271): 119190.
[13] Dworatzek E, Mahmoodzadeh S, Dworatzek E, et al. Targeted basic research to highlight the role of estrogen and estrogen receptors in the cardiovascular system[J]. Pharmacol Res, 2017, 119: 27-35.
[14] Quast A, Martian V, Bohnsack A, et al. Donor variation and sex hormone receptors in periodontal ligament cells[J]. Transplant Proceed, 2020, 122(105): 1026-1037.
[15] Xie D, Zhao J, Guo R, et al. Sevoflurane pre-conditioning ameliorates diabetic myocardial ischemia/reperfusion injury via differential regulation of p38 and ERK[J]. Sci Rep, 2020, 10(1): 23.
[16] Li W, Li Y, Chu Y, et al. PLCE1 promotes myocardial ischemia-reperfusion injury in H/R H9c2 cells and I/R rats by promoting inflammation[J]. Biosci Rep, 2019, 39(7): BSR20181613.
[17] Wang L, Niu H, Zhang J, et al. Homocysteine induces mitochondrial dysfunction and oxidative stress in myocardial ischemia/reperfusion injury through stimulating ROS production and the ERK1/2 signaling pathway[J]. Exp Ther Med, 2020, 20(2): 938-944.