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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.

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