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TRANSLATIONAL PHYSIOLOGY

Estrogen receptor- mediates acute myocardial protection in females

Departments of ¹Surgery and ²Cellular and Integrative Physiology; and ³Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana

Submitted 17 November 2005 ; accepted in final form 13 January 2006

	ABSTRACT

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Sex differences in myocardial recovery have been reported after acute ischemia and reperfusion injury. Estrogen and the estrogen receptor are critical determinants of cardiovascular sex differences. However, the mechanistic pathways responsible for these differences remain unknown. We hypothesized that estrogen receptor- is an important modulator of 1) myocardial functional recovery after ischemia and 2) inflammatory signaling via MAPK. To study this, adult male and female wild-type (WT) and estrogen receptor- knockout (ER1KO) mouse hearts were isolated, perfused via Langendorff model, and subjected to 20 min of ischemia and 60 min of reperfusion. Myocardial contractile function (left ventricular developed pressure and positive and negative first derivative of pressure) was continuously recorded. After ischemia-reperfusion, hearts were assessed for expression of inflammatory cytokines (ELISA) and activation of MAPK and caspase-3 (Western blot analysis). Data were analyzed with two-way ANOVA or Student's t-test, and P < 0.05 was statistically significant. ER1KO females exhibited significantly less functional recovery than WT females and were similar to WT males. Activated ERK was increased in female WT hearts compared with female ER1KO. Activated JNK was decreased in female WT hearts compared with female ER1KO. No significant differences were found between male WT, female WT, male ER1KO, and female ER1KO in activated p38 MAPK, proinflammatory cytokine expression, and proapoptotic signaling. Estrogen receptor- plays a role in the protection observed in the female heart. Differential activation of MAPK may mediate this protection. Further studies are necessary to delineate these mechanistic pathways.

cardiac ischemia; sex hormones; inflammation; mitogen-activated protein kinase

Two ER molecules have been identified: the original ER- and the more recently discovered ER- (23). Expression of ER- and ER- varies in different tissues and species (11). In murine as well as human myocardial tissue, the presence of ER- is well established (16, 19, 31). In contrast, Mendelsohn et al. (30) and others (13, 22, 45) have questioned whether murine hearts express ER-. This uncertainty regarding the expression of the ER in myocardium highlights the need to delineate the role of ER- and ER- in myocardial I/R injury.

Myocardial inflammation also plays a critical role in I/R injury and is characterized by the expression of inflammatory cytokines (7, 29) and the activation of the MAPK family, p38 MAPK, JNK, and extracellular signal-regulated protein kinase p42/p44 (ERK) (20). However, differences in the I/R response have been noted among these kinases; whereas activity of p38 MAPK and JNK was related to myocardial dysfunction (26), ERK activation was observed to improve cardiac functional recovery (20). Sex differences have also been observed in MAPK signaling (2, 21, 42), and estrogen has been associated with decreased p38 MAPK signaling (42, 43). No investigation has determined the role of the ER in MAPK signaling.

Therefore, we hypothesize that in female murine hearts, ER- confers cardioprotection after I/R and that ER- regulates cytokine expression, inhibits p38 MAPK and JNK signaling, activates ERK, and regulates apoptotic signaling in female myocardium subjected to I/R. The purpose of this study was to determine the effect of ER- on postischemic myocardial function, inflammatory signaling, and apoptotic signaling by using mice with a targeted mutation of ER-.

	MATERIALS AND METHODS

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Animals. A total of 20 strain C57BL/6J mice {10 with targeted mutation of ER- [ER- knockout (ER1KO)], transgenic mouse strain Tg(cre/Esr1)5Amc, and 10 wild type (WT) (Jackson Laboratory, Bar Harbor, ME)} were fed a standard diet and acclimated in a quiet quarantine room for 1 wk before the experiments. The animal protocol was reviewed and approved by the Indiana Animal Care and Use Committee of Indiana University. All animals received humane care in compliance with Guide for the Care and Use of Laboratory Animals, published by the National Institutes of Health (NIH Publications No. 85-23, Revised 1996).

All isolated mouse hearts were subjected to the same I/R protocol: 15-min equilibration period, 20-min global ischemia (37°C), and 60-min total reperfusion. Mouse hearts were divided into four experimental groups: normal females (n = 5), ER1KO females (n = 5), normal males (n = 5), and ER1KO males (n = 5).

Isolated heart preparation (Langendorff). Mice were anesthetized (pentobarbital sodium, 60 mg/kg ip) and heparinized (500 U ip), and hearts were rapidly excised via median sternotomy and placed in 4°C Krebs-Henseleit (KH) solution. The aorta was cannulated, and the heart was retrograde perfused in the isolated, isovolumetric Langendorff mode (70 mmHg) with KH solution (in mM: 11 dextrose, 110 NaCl, 1.2 CaCl₂, 4.7 KCl, 20.8 NaHCO₃, 1.18 KHPO₄, and 1.17 MgSO₄) at 37°C. The KH solution was bubbled with 95% O₂-5% CO₂ (Medipure) to achieve a PO₂ of 450–460 mmHg, PCO₂ of 39–41 mmHg, and pH of 7.39–7.41. Total ischemic time was <45 s. The perfusion buffer was continuously filtered through a 0.45-µm filter to remove particulates. A pulmonary arteriotomy and left atrial resection were performed before insertion of a water-filled latex balloon through the left atrium into the left ventricle. The preload volume (balloon volume) was held constant during the entire experiment to allow continuous recording of the left ventricular developed pressure. The balloon was adjusted to a mean left ventricular end-diastolic pressure of 8 mmHg (range 6–10 mmHg) during the initial equilibration. Pacing wires were fixed to the right atrium and left ventricle, and hearts were paced at 6 Hz, 3 V, 2 ms (350 beats/min) throughout perfusion. A three-way stopcock above the aortic root was used to create global ischemia, during which the heart was placed in a 37°C degassed organ bath. Coronary flow was measured by collecting pulmonary artery effluent. Data were continuously recorded using a PowerLab 8 preamplifier/digitizer (AD Instruments, Milford, MA) and an Apple G4 PowerPC computer (Apple Computer, Cupertino, CA). The maximal positive and negative values of the first derivative of pressure (+dP/dt and –dP/dt) were calculated with PowerLab software.

Coronary effluent lactate dehydrogenase activity. Coronary effluent (1 ml) was collected at 10, 20, 30, and 40 min into reperfusion and then frozen at –70°C until assay. The assay was performed with a lactate dehydrogenase (LDH) Cytotoxicity Detection Kit (Roche Diagnostics, Indianapolis, IN). The assay was performed according to the manufacturer's instructions. All samples were measured in duplicate.

Myocardial proinflammatory cytokine expression. Heart tissue and coronary effluent from various time points were homogenized separately in cold buffer containing 20 mM Tris (pH 7.5), 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 2.5 mM sodium pyrophosphate, 1 mM -glycerophosphate, 1 mM Na₃VO₄, 1 µg/ml leupeptin, and 1 mM PMSF and centrifuged at 12,000 rpm for 5 min. Myocardial TNF-, IL-1, and IL-6 in the cardiac tissue were determined by ELISA with a commercially available ELISA kit (R&D Systems, Minneapolis, MN). ELISA was performed according to the manufacturer's instructions. All samples and standards were measured in duplicate.

Western blotting. Western blot analysis was performed to measure MAPK and apoptosis-related proteins. Heart tissue was homogenized in cold buffer containing 20 mM Tris (pH 7.5), 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 2.5 mM sodium pyrophosphate, 1 mM -glycerophosphate, 1 mM Na₃VO₄, 1 µg/ml leupeptin, and 1 mM PMSF and centrifuged at 12,000 rpm for 5 min. The protein extracts (30 µg/lane) were subjected to electrophoresis on a 12% Tris·HCl gel from Bio-Rad and transferred to a nitrocellulose membrane, which was stained by Naphthol Blue-Black to confirm equal protein loading. The membranes were incubated in 5% dry milk for 1 h and then incubated with the following primary antibodies: p38 MAPK antibody, phosphor-p38 MAPK (Thr180/Tyr182) antibody, JNK antibody, phosphor-JNK (Thr183/Tyr185) antibody, ERK antibody, phosphor-ERK (Thr202/Tyr204) antibody (Cell Signaling Technology, Beverly, MA), caspase-3 (H-277) antibody (Santa Cruz Biotechnology, Santa Cruz, CA), Bcl-2 (Ab-4) antibody, and GAPDH antibody (Oncogene Research Products, San Diego, CA). Subsequently, the membranes were incubated with horseradish peroxidase-conjugated goat anti-rabbit or anti-mouse IgG secondary antibody. Detection was performed using SuperSignal West Pico stable peroxide solution (Pierce, Rockford, IL). Films were scanned with an Epson Perfection 3200 Scanner (Epson America, Long Beach, CA), and band density was analyzed with ImageJ software (NIH).

Presentation of data and statistical analysis. All reported values are means ± SE. Data were compared with the use of two-way ANOVA with post hoc Bonferroni test or Student's t-test (female WT vs. female ER1KO and male WT vs. male ER1KO). A two-tailed probability value of <0.05 was considered statistically significant. Representative gels are shown with all lanes/samples from the same gel for each respective figure.

	RESULTS

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Myocardial function. Maximum +dP/dt and –dP/dt were impaired at the start of reperfusion. Female ER1KO hearts demonstrated more depression of +dP/dt and elevation of –dP/dt compared with female WT hearts (Fig. 1). Male WT hearts also demonstrated more depression of +dP/dt and elevation of –dP/dt compared with female WT hearts. Male WT, male ER1KO, and female ER1KO hearts exhibited similar impairments of contractility and compliance.

View larger version (28K): [in this window] [in a new window]   Fig. 1. Changes in myocardial function after ischemia-reperfusion (I/R) in male wild-type (M WT) hearts, female wild-type hearts (F WT), male estrogen receptor- knockouts (M ER1KO), and female estrogen receptor- knockouts (F ER1KO). A: maximum positive first derivative of pressure (+dP/dt) (%equilibration). B: maximum –dP/dt (%equilibration). C: recovery of +dP/dt after I/R at end reperfusion (%equilibration). D: recovery of +dP/dt after I/R at end reperfusion (%equilibration). Results are means ± SE. *P < 0.05 at corresponding time points. P < 0.05, F WT vs. F ER1KO.

Myocardial MAPK signaling pathway after I/R. The myocardial activation of phosphorylated p38 (active), nonphosphorylated p38 (total) MAPK, phosphorylated JNK, nonphosphorylated JNK, phosphorylated ERK, and nonphosphorylated ERK were assessed by Western blot analysis (Figs. 2, 3, and 4). The phosphorylated forms of ERK were increased in female WT hearts compared with female ER1KO hearts. The phosphorylated forms of JNK were decreased in female WT hearts compared with female ER1KO hearts. Total p38 MAPK, activated p38 MAPK, total JNK, and total ERK were equivalent in female WT, female ER1KO, male WT, and male ER1KO hearts after I/R.

View larger version (36K): [in this window] [in a new window]   Fig. 2. I/R induced myocardial phosphorylation of p44/42 (ERK). Expression of activated ERK after I/R injury in M WT, F WT, M ER1KO, and F ER1KO is shown. A: representative immunoblots: row 1, phosphorylated (activated) ERK (p-ERK); row 2, total ERK. All samples were on the same membrane. B: densitometry data of p-ERK (%total ERK). Results are means ± SE. *P < 0.05 F WT vs. M WT; #P < 0.05 F WT vs. F ER1KO.

View larger version (33K): [in this window] [in a new window]   Fig. 3. I/R induced myocardial phosphorylation of JNK. Expression of activated JNK after I/R injury in M WT, F WT, M ER1KO, and F ER1KO is shown. A: representative immunoblots: row 1, phosphorylated (activated) JNK (p-JNK); row 2, total JNK. All samples were on the same membrane. B: densitometry data of p-JNK (%total JNK). Results are means ± SE. *P < 0.05 vs. M WT; #P < 0.05 F WT vs. F ER1KO.

View larger version (32K): [in this window] [in a new window]   Fig. 4. I/R induced myocardial phosphorylation of p38 MAPK. Expression of activated ERK after I/R injury in M WT, F WT, M ER1KO, and F ER1KO is shown. A: representative immunoblots: row 1, phosphorylated (activated) p38 MAPK (p-p38); row 2, total p38 MAPK. All samples were on the same membrane. B: densitometry data of p-p38 MAPK (%total p38 MAPK). Results are means ± SE.

View larger version (40K): [in this window] [in a new window]   Fig. 5. Myocardial expression of proapoptotic enzymes in M WT, F WT, M ER1KO, and F ER1KO. A: representative immunoblots. All samples were on the same membrane. B: densitometry data of caspase-3 (%GAPDH). Results are means ± SE.

View larger version (22K): [in this window] [in a new window]   Fig. 6. Effect on myocardial TNF-, IL-1, and IL-6 production after I/R in M WT, F WT, M ER1KO, and F ER1KO. E, equilibration; R, reperfusion. Results are means ± SE. *P < 0.05, F WT vs. M WT.

	DISCUSSION

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ER- may play an important role in modulating the contractile dysfunction induced by I/R injury for several reasons. Previously, we (43) demonstrated that 17-estradiol, a nonselective ER ligand, increased functional recovery and decreased inflammation and apoptosis after acute ischemia in males as well as ovariectomized females. Recently, Booth et al. (6) found that a selective ER- agonist, 4,4',4''-[4-propyl-(1H)-pyrazole-1,3,5-triyl]tris-phenol, reduced infarct size, release of troponin I, and deposit of the membrane attack complex after I/R in rabbit hearts. ICI-182780 and ZM-182780, both potent ER antagonists, also have been found to reverse the cardioprotection conferred by 17-estradiol (35) and selective ER- agonists (6, 37). A study (47) limited to male mice (with presumably lower estrogen levels) also found significantly lower coronary flow rate in ER- knockouts. Indeed, the results of this study corroborate the latter indirect evidence that ER- mediates cardioprotection in females; female ER1KO hearts demonstrated a statistically significant decrease in functional recovery of contractility (+dP/dt) and compliance (–dP/dt) in comparison with female WT hearts. Recently, both estradiol (36) as well as 16-LE2 (37), an ER- selective ligand, significantly reduced cardiac hypertrophy and increased cardiac output. Thus it is possible that ER- mediates improved contractility and compliance in females via a reduction in cardiac hypertrophy and infarct reduction.

MAPKs are critically involved in regulatory signaling pathways that ultimately lead to inflammation and cardiac hypertrophy (9). Activation of p38 MAPK and JNK is a critical step in the generation of deleterious myocardial inflammation after I/R injury, whereas ERK activation has been found to improve cardiac functional recovery (20). Similarly, transfection of cardiomyocytes with adenoviral vectors expressing upstream activators for p38 MAPK and JNK induces transcriptional and morphological changes associated with the hypertrophy (44, 46); activation of ERK has not been associated with myocardial hypertrophy (38, 39). Sex differences have been noted in MAPK signaling (2, 21, 42). In particular, estrogen has been found to modulate activation of the MAPK signal cascade (42, 43). Previously, we (43) determined that estrogen decreased MAPK inflammatory signaling, inflammatory cytokine expression, and apoptotic signaling after acute ischemia in males as well as ovariectomized females. However, Migliaccio et al. (32) determined that the activation of MAPK pathway by estrogen requires the ligand occupancy of the ER. Indeed, in this study, ER- was found to increase protective ERK1/2 activation and decrease proapoptotic JNK activation during myocardial ischemia in females; no significant differences were found in p38 MAPK activation in female WT and female ER1KO hearts. This differential activation confirms previous findings that estradiol induced a rapid activation of ERK and JNK but had only a marginal effect on p38 MAPK activation (33). Therefore, these findings suggest that ER- may mediate reduced cardiac hypertrophy and inflammation via differential activation of the MAPK family.

We found no significant difference in the myocardial production of TNF-, IL-1, IL-6, and caspase-3 between female WT and female ER1KO hearts, as well as between male WT and male ER1KO hearts. Previously, exogenous estrogen decreased myocardial inflammatory cytokine production and increased postischemic cardiac function, suggesting that estrogen exerts a protective effect on myocardium via decreased myocardial inflammation (43). This discrepancy in myocardial inflammatory cytokine production between estrogen exposure and ER- exposure may reflect an ER-independent mechanism. It is widely recognized that estrogen binds to intracellular receptors and modulates transcription and protein synthesis, triggering genomic events responsible for physiological effects (5). However, accumulating data suggest that some metabolites of estradiol are biologically active and mediate multiple effects on the cardiovascular systems that are largely independent of ERs; catecholestradiols and methoxyestradiols are implicated in this process (12). In other systems, investigators have found that the protective effect of estrogen on inflammatory cytokine production was not dependent on ER- signaling (15, 24). Thus this discrepancy in cytokine production between estrogen exposure and ER- exposure intimates that estrogen may exert its protective effects on myocardium via different receptor- dependent and -independent pathways.

This study did not address the role of ER- in myocardial I/R injury in murine animals. Several investigators (13, 22, 45) have questioned whether murine hearts express ER-. Oliveira et al. (34) found that ICI-182780, an ER receptor antagonist, has no effect on ER- in rats. Although Gabel et al. (14) suggest that ER- in rats plays a role in sex differences in I/R injury under hypercontractile conditions, no differences were discovered under normal contractile conditions. This study demonstrates that, under normal contractile conditions, ER1KO hearts exhibited significantly less functional recovery than those of WT females and were similar to those of WT males. Whether similar findings can be applied to ER- remains to be determined and can be a potential aspect to address in future studies.

There still remains a great deal of controversy over the role of sex difference and injury. This study confirms the protective effects of ER- in females. This may also lend insight into the mechanistic pathways behind the variation in clinical outcomes between males and females after myocardial infarction. Perhaps modification of ER--dependent mechanisms associated with I/R will alter the myocardial response to ischemia in menopausal females and, potentially, males.

	GRANTS

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This work was supported in part by National Institutes of Health Grant R01- GM-070628 (to D. R. Meldrum), an American Heart Association Postdoctoral Fellowship (to M. Wang), the Clarian Values Fund (to D. R. Meldrum), the Showalter Trust (to D. R. Meldrum), and the Cryptic Masons Medical Research Foundation (to D. R. Meldrum and M. Wang).

	FOOTNOTES

 

Address for reprint requests and other correspondence: D. R. Meldrum, Dept. of Surgery, Indiana University School of Medicine, 545 Barnhill Dr., Emerson Hall 215, Indianapolis, IN 46202 (e-mail: dmeldrum{at}iupui.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^* M. Wang and P. Crisostomo contributed equally to this work.

	REFERENCES

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1. Adams KF Jr, Sueta CA, Gheorghiade M, O'Connor CM, Schwartz TA, Koch GG, Uretsky B, Swedberg K, McKenna W, Soler-Soler J, and Califf RM. Gender differences in survival in advanced heart failure. Insights from the FIRST study. Circulation 99: 1816–1821, 1999.[Abstract/Free Full Text]
2. Angele MK, Nitsch S, Knoferl MW, Ayala A, Angele P, Schildberg FW, Jauch KW, and Chaudry IH. Sex-specific p38 MAP kinase activation following trauma-hemorrhage: involvement of testosterone and estradiol. Am J Physiol Endocrinol Metab 285: E189–E196, 2003.[Abstract/Free Full Text]
3. Angele MK, Schwacha MG, Ayala A, and Chaudry IH. Effect of gender and sex hormones on immune responses following shock. Shock 14: 81–90, 2000.[ISI][Medline]
4. Baker L, Meldrum KK, Wang M, Sankula R, Vanam R, Raiesdana A, Tsai BM, Hile K, Brown JW, and Meldrum DR. The role of estrogen in cardiovascular disease. J Surg Res 115: 325–344, 2003.[CrossRef][ISI][Medline]
5. Beato M and Klug J. Steroid hormone receptors: an update. Hum Reprod Update 6: 225–236, 2000.[Abstract/Free Full Text]
6. Booth EA, Obeid NR, and Lucchesi BR. Activation of estrogen receptor- protects the in vivo rabbit heart from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 289: H2039–H2047, 2005.[Abstract/Free Full Text]
7. Cain BS, Meldrum DR, Dinarello CA, Meng X, Joo KS, Banerjee A, and Harken AH. Tumor necrosis factor- and interleukin-1 synergistically depress human myocardial function. Crit Care Med 27: 1309–1318, 1999.[CrossRef][ISI][Medline]
8. Cavasin MA, Tao Z, Menon S, and Yang XP. Gender differences in cardiac function during early remodeling after acute myocardial infarction in mice. Life Sci 75: 2181–2192, 2004.[CrossRef][ISI][Medline]
9. Clerk A, Michael A, and Sugden PH. Stimulation of the p38 mitogen-activated protein kinase pathway in neonatal rat ventricular myocytes by the G protein-coupled receptor agonists, endothelin-1 and phenylephrine: a role in cardiac myocyte hypertrophy? J Cell Biol 142: 523–535, 1998.[Abstract/Free Full Text]
10. Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE, and Hennekens CH. Menopause and the risk of coronary heart disease in women. N Engl J Med 316: 1105–1110, 1987.[Abstract]
11. Couse JF, Lindzey J, Grandien K, Gustafsson JA, and Korach KS. Tissue distribution and quantitative analysis of estrogen receptor- (ER) and estrogen receptor- (ER) messenger ribonucleic acid in the wild-type and ER-knockout mouse. Endocrinology 138: 4613–4621, 1997.[Abstract/Free Full Text]
12. Dubey RK, Tofovic SP, and Jackson EK. Cardiovascular pharmacology of estradiol metabolites. J Pharmacol Exp Ther 308: 403–409, 2004.[Abstract/Free Full Text]
13. Forster C, Kietz S, Hultenby K, Warner M, and Gustafsson JA. Characterization of the ER^-/- mouse heart. Proc Natl Acad Sci USA 101: 14234–14239, 2004.[Abstract/Free Full Text]
14. Gabel SA, Walker VR, London RE, Steenbergen C, Korach KS, and Murphy E. Estrogen receptor beta mediates gender differences in ischemia/reperfusion injury. J Mol Cell Cardiol 38: 289–297, 2005.[CrossRef][Medline]
15. Garidou L, Laffont S, Douin-Echinard V, Coureau C, Krust A, Chambon P, and Guery JC. Estrogen receptor signaling in inflammatory leukocytes is dispensable for 17-estradiol-mediated inhibition of experimental autoimmune encephalomyelitis. J Immunol 173: 2435–2442, 2004.[Abstract/Free Full Text]
16. Grohe C, Kahlert S, Lobbert K, and Vetter H. Expression of oestrogen receptor and in rat heart: role of local oestrogen synthesis. J Endocrinol 156: R1–R7, 1998.[Abstract]
17. Guerra S, Leri A, Wang X, Finato N, Di Loreto C, Beltrami CA, Kajstura J, and Anversa P. Myocyte death in the failing human heart is gender dependent. Circ Res 85: 856–866, 1999.[Abstract/Free Full Text]
18. Horton JW, White DJ, and Maass DL. Gender-related differences in myocardial inflammatory and contractile responses to major burn trauma. Am J Physiol Heart Circ Physiol 286: H202–H213, 2004.[Abstract/Free Full Text]
19. Jankowski M, Rachelska G, Donghao W, McCann SM, and Gutkowska J. Estrogen receptors activate atrial natriuretic peptide in the rat heart. Proc Natl Acad Sci USA 98: 11765–11770, 2001.[Abstract/Free Full Text]
20. Khan TA, Bianchi C, Ruel M, Voisine P, and Sellke FW. Mitogen-activated protein kinase pathways and cardiac surgery. J Thorac Cardiovasc Surg 127: 806–811, 2004.[Abstract/Free Full Text]
21. Kher A, Wang M, Tsai BM, Pitcher JM, Greenbaum ES, Nagy RD, Patel KM, Wairiuko GM, Markel TA, and Meldrum DR. Sex differences in the myocardial inflammatory response to acute injury. Shock 23: 1–10, 2005.[ISI][Medline]
22. Kuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, and Gustafsson JA. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors and . Endocrinology 138: 863–870, 1997.[Abstract/Free Full Text]
23. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, and Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93: 5925–5930, 1996.[Abstract/Free Full Text]
24. Lambert KC, Curran EM, Judy BM, Milligan GN, Lubahn DB, and Estes DM. Estrogen receptor (ER) deficiency in macrophages results in increased stimulation of CD4⁺ T cells while 17-estradiol acts through ER to increase IL-4 and GATA-3 expression in CD4⁺ T cells independent of antigen presentation. J Immunol 175: 5716–5723, 2005.[Abstract/Free Full Text]
25. Lee TM, Su SF, Tsai CC, Lee YT, and Tsai CH. Cardioprotective effects of 17-estradiol produced by activation ofmitochondrial ATP-sensitive K⁺ channels in canine hearts. J Mol Cell Cardiol 32: 1147–1158, 2000.[CrossRef][ISI][Medline]
26. Liao P, Wang SQ, Wang S, Zheng M, Zhang SJ, Cheng H, Wang Y, and Xiao RP. p38 Mitogen-activated protein kinase mediates a negative inotropic effect in cardiac myocytes. Circ Res 90: 190–196, 2002.[Abstract/Free Full Text]
27. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, and Evans RM. The nuclear receptor superfamily: the second decade. Cell 83: 835–839, 1995.[CrossRef][ISI][Medline]
28. Matsumura K, Jeremy RW, Schaper J, and Becker LC. Progression of myocardial necrosis during reperfusion of ischemic myocardium. Circulation 97: 795–804, 1998.[Abstract/Free Full Text]
29. Meldrum DR. Tumor necrosis factor in the heart. Am J Physiol Regul Integr Comp Physiol 274: R577–R595, 1998.[Abstract/Free Full Text]
30. Mendelsohn ME and Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science 308: 1583–1587, 2005.[Abstract/Free Full Text]
31. Mendelsohn ME and Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 340: 1801–1811, 1999.[Free Full Text]
32. Migliaccio A, Di Domenico M, Castoria G, de Falco A, Bontempo P, Nola E, and Auricchio F. Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells. EMBO J 15: 1292–1300, 1996.[ISI][Medline]
33. Nuedling S, Kahlert S, Loebbert K, Meyer R, Vetter H, and Grohe C. Differential effects of 17-estradiol on mitogen-activated protein kinase pathways in rat cardiomyocytes. FEBS Lett 454: 271–276, 1999.[CrossRef][ISI][Medline]
34. Oliveira CA, Nie R, Carnes K, Franca LR, Prins GS, Saunders PT, and Hess RA. The antiestrogen ICI 182,780 decreases the expression of estrogen receptor- but has no effect on estrogen receptor- and androgen receptor in rat efferent ductules (Abstract). Reprod Biol Endocrinol 1: 75, 2003.[CrossRef][Medline]
35. Patten RD, Pourati I, Aronovitz MJ, Baur J, Celestin F, Chen X, Michael A, Haq S, Nuedling S, Grohe C, Force T, Mendelsohn ME, and Karas RH. 17-Estradiol reduces cardiomyocyte apoptosis in vivo and in vitro via activation of phospho-inositide-3 kinase/Akt signaling. Circ Res 95: 692–699, 2004.[Abstract/Free Full Text]
36. Pedram A, Razandi M, Aitkenhead M, and Levin ER. Estrogen inhibits cardiomyocyte hypertrophy in vitro. Antagonism of calcineurin-related hypertrophy through induction of MCIP1. J Biol Chem 280: 26339–26348, 2005.[Abstract/Free Full Text]
37. Pelzer T, Jazbutyte V, Hu K, Segerer S, Nahrendorf M, Nordbeck P, Bonz AW, Muck J, Fritzemeier KH, Hegele-Hartung C, Ertl G, and Neyses L. The estrogen receptor- agonist 16-LE2 inhibits cardiac hypertrophy and improves hemodynamic function in estrogen-deficient spontaneously hypertensive rats. Cardiovasc Res 67: 604–612, 2005.[Abstract/Free Full Text]
38. Post GR, Goldstein D, Thuerauf DJ, Glembotski CC, and Brown JH. Dissociation of p44 and p42 mitogen-activated protein kinase activation from receptor-induced hypertrophy in neonatal rat ventricular myocytes. J Biol Chem 271: 8452–8457, 1996.[Abstract/Free Full Text]
39. Ramirez MT, Sah VP, Zhao XL, Hunter JJ, Chien KR, and Brown JH. The MEKK-JNK pathway is stimulated by ₁-adrenergic receptor and Ras activation and is associated with in vitro and in vivo cardiac hypertrophy. J Biol Chem 272: 14057–14061, 1997.[Abstract/Free Full Text]
40. Rossouw JE. Hormones, genetic factors, and gender differences in cardiovascular disease. Cardiovasc Res 53: 550–557, 2002.[Free Full Text]
41. Schwarzenberger JC, Sun LS, Pesce MA, Heyer EJ, Delphin E, Almeida GM, and Wood M. Sex-based differences in serum cardiac troponin I, a specific marker for myocardial injury, after cardiac surgery. Crit Care Med 31: 689–693, 2003.[CrossRef][ISI][Medline]
42. Wang M, Baker L, Tsai BM, Meldrum KK, and Meldrum DR. Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury. Am J Physiol Endocrinol Metab 288: E321–E326, 2005.[Abstract/Free Full Text]
43. Wang M, Tsai BM, Reiger KM, Brown JW, and Meldrum DR. 17-Beta-estradiol decreases p38 MAPK-mediated myocardial inflammation and dysfunction following acute ischemia. J Mol Cell Cardiol 40: 205–212, 2006.[CrossRef][ISI][Medline]
44. Wang Y, Huang S, Sah VP, Ross J Jr, Brown JH, Han J, and Chien KR. Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family. J Biol Chem 273: 2161–2168, 1998.[Abstract/Free Full Text]
45. Yang SH, Liu R, Perez EJ, Wen Y, Stevens SM Jr, Valencia T, Brun-Zinkernagel AM, Prokai L, Will Y, Dykens J, Koulen P, and Simpkins JW. Mitochondrial localization of estrogen receptor . Proc Natl Acad Sci USA 101: 4130–4135, 2004.[Abstract/Free Full Text]
46. Zechner D, Thuerauf DJ, Hanford DS, McDonough PM, and Glembotski CC. A role for the p38 mitogen-activated protein kinase pathway in myocardial cell growth, sarcomeric organization, and cardiac-specific gene expression. J Cell Biol 139: 115–127, 1997.[Abstract/Free Full Text]
47. Zhai P, Eurell TE, Cooke PS, Lubahn DB, and Gross DR. Myocardial ischemia-reperfusion injury in estrogen receptor- knockout and wild-type mice. Am J Physiol Heart Circ Physiol 278: H1640–H1647, 2000.[Abstract/Free Full Text]
48. Zhai P, Eurell TE, Cotthaus R, Jeffery EH, Bahr JM, and Gross DR. Effect of estrogen on global myocardial ischemia-reperfusion injury in female rats. Am J Physiol Heart Circ Physiol 279: H2766–H2775, 2000.[Abstract/Free Full Text]

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