Estrogen Regulates Angiotensin II Receptor Expression Patterns and Protects the Heart from Ischemic Injury in Female Rats

Overview

Journal Biol Reprod

Publisher Oxford University Press

Specialty Reproductive Medicine

Date 2015 May 15

PMID 25972014

Citations 18

Authors

Qin Xue

Daliao Xiao

Lubo Zhang

Affiliations

Soon will be listed here.

Abstract

Previous studies have shown that female offspring are resistant to fetal stress-induced programming of ischemic-sensitive phenotype in the heart; however, the mechanisms responsible remain unclear. The present study tested the hypothesis that estrogen plays a role in protecting females in fetal programming of increased heart vulnerability. Pregnant rats were divided into normoxic and hypoxic (10.5% O2 from Day 15 to 21 of gestation) groups. Ovariectomy (OVX) and estrogen (E2) replacement were performed in 8-wk-old female offspring. Hearts of 4-mo-old females were subjected to ischemia and reperfusion injury in a Langendorff preparation. OVX significantly decreased postischemic recovery of left ventricular function and increased myocardial infarction, and no difference was observed between normoxic and hypoxic groups. The effect of OVX was rescued by E2 replacement. OVX decreased the binding of glucocorticoid receptor (GR) to glucocorticoid response elements at angiotensin II type 1 (Agtr1) and type 2 (Agtr2) receptor promoters, resulting in a decrease in Agtr1 and an increase in Agtr2 in the heart. Additionally, OVX decreased estrogen receptor (ER) expression in the heart and inhibited ER/GR interaction in binding to glucocorticoid response elements at the promoters. Consistent with the changes in Agtrs, OVX significantly decreased Prkce abundance in the heart. These OVX-induced changes were abrogated by E2 replacement. The results indicate that estrogen is not directly responsible for the sex dimorphism in fetal programming of heart ischemic vulnerability but suggest a novel mechanism of estrogen in regulating cardiac Agtr1/Agtr2 expression patterns and protecting female hearts against ischemia and reperfusion injury.

Citing Articles

The molecular mechanisms in prenatal drug exposure-induced fetal programmed adult cardiovascular disease.

Wu T, Zhou K, Hua Y, Zhang W, Li Y Front Pharmacol. 2023; 14:1164487.

PMID: 37153765 PMC: 10157035. DOI: 10.3389/fphar.2023.1164487.

Role of Estrogen Receptor-Positive/Negative Ratios in Regulating Breast Cancer.

Li Y, Zhang H, Jiang T, Li P Evid Based Complement Alternat Med. 2022; 2022:7833389.

PMID: 36118080 PMC: 9477638. DOI: 10.1155/2022/7833389.

Estrogen normalizes maternal HFD-induced vascular dysfunction in offspring by regulating ATR.

Chen F, Zhao R, Zhang H, Huang C, Liu Y, Xue Q Hypertens Res. 2022; 45(11):1743-1753.

PMID: 35999282 DOI: 10.1038/s41440-022-01002-2.

Prenatal Hypoxia Affects Foetal Cardiovascular Regulatory Mechanisms in a Sex- and Circadian-Dependent Manner: A Review.

Sutovska H, Babarikova K, Zeman M, Molcan L Int J Mol Sci. 2022; 23(5).

PMID: 35270026 PMC: 8910900. DOI: 10.3390/ijms23052885.

Neurodegenerative Disease: Roles for Sex, Hormones, and Oxidative Stress.

Sumien N, Cunningham J, Davis D, Engelland R, Fadeyibi O, Farmer G Endocrinology. 2021; 162(11).

PMID: 34467976 PMC: 8462383. DOI: 10.1210/endocr/bqab185.

References

Hinojosa-Laborde C, Mifflin S . Sex differences in blood pressure response to intermittent hypoxia in rats. Hypertension. 2005; 46(4):1016-21. DOI: 10.1161/01.HYP.0000175477.33816.f3. View

Chen M, Xiong F, Zhang L . Promoter methylation of Egr-1 site contributes to fetal hypoxia-mediated PKCε gene repression in the developing heart. Am J Physiol Regul Integr Comp Physiol. 2013; 304(9):R683-9. PMC: 3652077. DOI: 10.1152/ajpregu.00461.2012. View

Byers M, Zangl A, Phernetton T, Lopez G, Chen D, Magness R . Endothelial vasodilator production by ovine uterine and systemic arteries: ovarian steroid and pregnancy control of ERalpha and ERbeta levels. J Physiol. 2005; 565(Pt 1):85-99. PMC: 1464491. DOI: 10.1113/jphysiol.2005.085753. View

Fang Z, Carlson S, Chen Y, Oparil S, Wyss J . Estrogen depletion induces NaCl-sensitive hypertension in female spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol. 2001; 281(6):R1934-9. DOI: 10.1152/ajpregu.2001.281.6.R1934. View

Shinmura K, Nagai M, Tamaki K, Bolli R . Loss of ischaemic preconditioning in ovariectomized rat hearts: possible involvement of impaired protein kinase C epsilon phosphorylation. Cardiovasc Res. 2008; 79(3):387-94. PMC: 2492728. DOI: 10.1093/cvr/cvn086. View

Diaz R, Wilson G . Selective blockade of AT1 angiotensin II receptors abolishes ischemic preconditioning in isolated rabbit hearts. J Mol Cell Cardiol. 1997; 29(1):129-39. DOI: 10.1006/jmcc.1996.0258. View

Mendelsohn M, Karas R . The protective effects of estrogen on the cardiovascular system. N Engl J Med. 1999; 340(23):1801-11. DOI: 10.1056/NEJM199906103402306. View

Zhai P, Eurell T, Cotthaus R, Jeffery E, Bahr J, Gross D . Effect of estrogen on global myocardial ischemia-reperfusion injury in female rats. Am J Physiol Heart Circ Physiol. 2000; 279(6):H2766-75. DOI: 10.1152/ajpheart.2000.279.6.H2766. View

Oparil S, Chen S, Chen Y, Durand J, Allen L, Thompson J . Estrogen attenuates the adventitial contribution to neointima formation in injured rat carotid arteries. Cardiovasc Res. 2000; 44(3):608-14. DOI: 10.1016/s0008-6363(99)00240-0. View

10.

Meyer K, Zhang H, Zhang L . Direct effect of cocaine on epigenetic regulation of PKCepsilon gene repression in the fetal rat heart. J Mol Cell Cardiol. 2009; 47(4):504-11. PMC: 2739252. DOI: 10.1016/j.yjmcc.2009.06.004. View

11.

Krishnamurthi K, Verbalis J, Zheng W, Wu Z, Clerch L, Sandberg K . Estrogen regulates angiotensin AT1 receptor expression via cytosolic proteins that bind to the 5' leader sequence of the receptor mRNA. Endocrinology. 1999; 140(11):5435-8. DOI: 10.1210/endo.140.11.7242. View

12.

Netuka I, Szarszoi O, Maly J, Besik J, Neckar J, Kolar F . Effect of perinatal hypoxia on cardiac tolerance to acute ischaemia in adult male and female rats. Clin Exp Pharmacol Physiol. 2006; 33(8):714-9. DOI: 10.1111/j.1440-1681.2006.04423.x. View

13.

Baiardi G, Macova M, Armando I, Ando H, Tyurmin D, Saavedra J . Estrogen upregulates renal angiotensin II AT1 and AT2 receptors in the rat. Regul Pept. 2004; 124(1-3):7-17. DOI: 10.1016/j.regpep.2004.06.021. View

14.

Hall J, Couse J, Korach K . The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem. 2001; 276(40):36869-72. DOI: 10.1074/jbc.R100029200. View

15.

Uht R, Anderson C, Webb P, Kushner P . Transcriptional activities of estrogen and glucocorticoid receptors are functionally integrated at the AP-1 response element. Endocrinology. 1997; 138(7):2900-8. DOI: 10.1210/endo.138.7.5244. View

16.

Ping P, Song C, Zhang J, Guo Y, Cao X, Li R . Formation of protein kinase C(epsilon)-Lck signaling modules confers cardioprotection. J Clin Invest. 2002; 109(4):499-507. PMC: 150872. DOI: 10.1172/JCI13200. View

17.

Dignam J, Lebovitz R, Roeder R . Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983; 11(5):1475-89. PMC: 325809. DOI: 10.1093/nar/11.5.1475. View

18.

Hadoke P, Lindsay R, Seckl J, Walker B, Kenyon C . Altered vascular contractility in adult female rats with hypertension programmed by prenatal glucocorticoid exposure. J Endocrinol. 2006; 188(3):435-42. DOI: 10.1677/joe.1.06506. View

19.

Hale , Birnbaum , Kloner . Estradiol, Administered Acutely, Protects Ischemic Myocardium in Both Female and Male Rabbits. J Cardiovasc Pharmacol Ther. 1997; 2(1):47-52. DOI: 10.1177/107424849700200106. View

20.

Lentini E, Kasahara M, Arver S, Savic I . Sex differences in the human brain and the impact of sex chromosomes and sex hormones. Cereb Cortex. 2012; 23(10):2322-36. DOI: 10.1093/cercor/bhs222. View