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Am J Physiol Endocrinol Metab 293: E872-E877, 2007. First published June 26, 2007; doi:10.1152/ajpendo.00251.2007
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TRANSLATIONAL PHYSIOLOGY

Sex differences in endothelial STAT3 mediate sex differences in myocardial inflammation

Meijing Wang,2 Wenjun Zhang,3 Paul Crisostomo,2 Troy Markel,2 Kirstan K. Meldrum,4 Xin Y. Fu,3 and Daniel R. Meldrum1,2

Departments of 1Cellular and Integrative Physiology, 2Surgery, 3Microbiology and Immunology, and 4Urology, Indiana University School of Medicine, Indianapolis, Indiana

Submitted 25 April 2007 ; accepted in final form 15 June 2007


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Recent studies have shown that females have improved myocardial functional recovery, TNF receptor 1 (TNFR1) signaling resistance, and increased STAT3 phosphorylation following acute ischemia/reperfusion (I/R) compared with males. We hypothesized that 1) STAT3 deficiency in endothelial cells (EC) impairs myocardial functional recovery in both sexes, 2) EC STAT3 deficiency equalizes sex differences in functional recovery, and 3) knockout of EC STAT3 decreases activation of myocardial STAT3 and increases p38 MAPK activation following acute I/R. Isolated male and female mouse hearts from WT and EC STAT3 knockout (STAT3KO) were subjected to 20-min ischemia/60-min reperfusion, and ± dP/dt were continuously recorded. Heart tissue was analyzed for the active forms of STAT3 and p38 MAPK as well as expression of caspase-8 (Western blot) following I/R. EC STATKO had significantly decreased myocardial functional recovery in both sexes (%recovered +dP/dt: male 51.6 ± 3.1 vs. 32.1 ± 13.1%, female 79.1 ± 3.6 vs. 43.6 ± 9.1%; –dP/dt: male 52.2 ± 3.3 vs. 28.9 ± 12%, female 75.2 ± 4.1 vs. 38.6 ± 10%). In addition, EC STAT3KO neutralized sex differences in myocardial function, which existed in WT mice. Interestingly, EC STAT3 deficiency decreased myocardial STAT3 activation but increased myocardial p38 MAPK activation in both sexes; however, this was seen to a greater degree in females. We conclude that EC STAT3 deficiency resulted in decreased recovery of myocardial function in both sexes and neutralized sex differences in myocardial functional recovery following I/R. This observation was associated with decreased activation of myocardial STAT3 and increased activation of p38 MAPK in EC STAT3KO heart after I/R.

ischemia/reperfusion; signal transducer and activator of transcription 3; myocardial function

SEX-SPECIFIC DIFFERENCES have been noted in cardiovascular disease (20). Clinically, females have a lower incidence of heart failure and a higher rate of heart failure survival (31). Similarly, animal studies from our group have demonstrated that females have better myocardial functional recovery (33), TNF receptor 1 (TNFR1) signaling resistance, and increased myocardial suppressor of cytokine signaling (SOCS)-3 expression following ischemia and reperfusion (I/R) compared with males (35). Although sex hormones have been thought to play an important role in the sex differences associated with myocardial infarction, the specific molecular and cellular signals involved in initiating these sex differences in the ischemic myocardium remain unclear.

Signal transducer and activator of transcription 3 (STAT3) has been implicated in a variety of cellular functions, including cell survival, proliferation, apoptosis, and inflammation (6, 7, 30, 37). Given that I/R induces a complex pathological and physiological process in the heart (14), one may assume that the STAT3 pathway may be involved in mediating the myocardial response to I/R injury. Indeed, accumulated evidence has indicated that STAT3 can be activated by ischemic/oxidative stress and that this signaling pathway exerts cardioprotection in ischemic heart (11, 21). Blocking the STAT3 pathway has been shown to enhance myocardial injury after an infarction (22). Evidence from cardiomyocyte-restricted ablation of STAT3 mice further indicates that STAT3 protects the heart from ischemic injury by suppressing cardiomyocyte apoptosis and inducing local growth factor production (11). However, no information exists regarding the effect of endothelial cell (EC) STAT3 on myocardial functional recovery following I/R. Numerous endothelial cells are present within the heart, and they may therefore mediate the myocardial immune response through cell surface or local cytokine production during injury (24, 25).

In this study, we hypothesized that EC STAT3 ablation would impair postischemic myocardial function and equalize sex differences in functional recovery and activation of myocardial STAT3 and p38 MAPK following acute I/R.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals. The STAT3 deficiency mouse line was C57B6 background and has been described previously (38). Briefly, STAT3 was deleted from hematopoietic cells by crossing STAT3 allele-floxed mouse with a Tie-2 promoter-driving Cre expression mouse. Four- to six-week-old wild-type (WT) and conditioned STAT3 knockout (KO) mice were maintained in a quiet quarantine room after birth. 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 the Guide for the Care and Use of Laboratory Animals (NIH publication No. 85-23, revised 1985).

A total of 23 isolated mouse hearts (n = 6/group for male mice, n = 8 for female WT, and n = 3 for female STAT3KO) were subjected to the same I/R protocol: a 15-min equilibration period, 20 min of global ischemia (37°C), and 60 min of reperfusion.

Isolated heart preparation (Langendorff) and measurement of cardiac function. Experiments were performed by use of a Langendorff apparatus as described previously for use in mouse heart. Briefly, 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 solution. The aorta was cannulated, and the heart was perfused with oxygenated (95% O2-5% CO2) Krebs-Henseleit solution (37°C). 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 (LVDP). A three-way stopcock above the aortic root was used to create global ischemia, at which time the heart was placed in a 37°C degassed organ bath. Hearts were paced at 400 beats/min during equilibration and reperfusion, and pacing was reinitiated after 3 min of reperfusion. 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 using PowerLab software.

Lactate dehydrogenase assay. Elevated lactate dehydrogenase (LDH) release indicates cell damage and tissue injury. Coronary effluent was collected and stored at –80°C until enzymatic analysis for LDH activity was determined by using a commercially available kit (Cytotoxicity Detection Kit-LDH; Roche Diagnostics, Indianapolis, IN). The LDH assay 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 STAT3, p38 MAP kinases, and caspase-8 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 beta-glycerophosphate, 1 mM Na3VO4, 1 µg/ml leupeptin, and1 mM PMSF and centrifuged at 12,000 rpm for 10 min. The protein extracts (20 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: STAT3, phospho-STAT3 (Tyr-), p38 MAP kinase, phospho-p38 MAP kinase (Thr180/Tyr182; Cell Signaling Technology, Beverly, MA), caspase-8 (Santa Cruz Biotechnology, Santa Cruz, CA), and GAPDH (Biodesign International, Saco, Maine) followed by incubation with horseradish peroxidase-conjugated goat anti-rabbit or anti-mouse IgG secondary antibody. Protein bands were detected using supersignal west pico stable peroxide solution (Pierce, Rockford, IL). Films were scanned using an Epson Perfection 3200 Scanner (Epson America, Long Beach, CA), and band density was analyzed using ImageJ software (NIH).

Myocardial TNF, IL-1beta, and IL-6. Myocardial TNF, IL-1beta, and IL-6 in cardiac tissue were determined by enzyme-linked immunosorbent assay (ELISA) using a commercially available ELISA set (R&D Systems, Minneapolis, MN). ELISA was performed according to the manufacturer's instructions. All samples and standards were measured in duplicate.

Presentation of data and statistical analysis. All reported values are means ± SE. Data were compared using two-way analysis of variance with post hoc Bonferroni test or Student's t-test. A two-tailed probability value of <0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Myocardial function in mice lacking STAT3 expression following I/R. I/R resulted in markedly impaired +dP/dt (contractility) and –dP/dt (compliance) in both WT and STAT3KO mouse hearts in both sexes. However, recovery of +dP/dt and –dP/dt in the postischemic period was significantly lower in STAT3KO (represented as %equilibration: male 33.3 ± 9.3, female 43.6 ± 9.1%) than in WT (male 53.3 ± 3.1, female 79.1 ± 3.6%) in both sexes (Fig. 1). In addition, EC STAT3KO neutralized the previously observed sex differences in myocardial functional recovery following I/R, which existed in WT hearts.


Figure 1
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  		Fig. 1. Changes in myocardial function following ischemia and reperfusion (I/R) in wild-type (WT) and endothelial cell (EC) STAT3-ablated mouse hearts perfused with modified Krebs-Henseleit solution. A: +dP/dt; B: –dP/dt. Results are means ± SE and are represented as %equilibration (eq). *P < 0.05 vs. M WT; #, {nabla}P < 0.05 vs. WT.

 
Furthermore, elevated LDH was observed in the coronary effluent after 20 min of global ischemia. STAT3 deficiency resulted in increased LDH leakage from injured myocardium compared with WT in both sexes (Fig. 2), which is in line with worse myocardial function in STAT3KO heart following I/R.


Figure 2
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  		Fig. 2. Lactate dehydrogenase (LDH) release in coronary effluent following I/R in both sexes. Value shown is equilibration: 10, 20, and 60 min of reperfusion, respectively. Results are means ± SE.

 
Activation of myocardial STAT3 and p38 MAPK following I/R. Myocardial phosphorylated/active STAT3 and p38, as well as the nonphosphorylated/total STAT3 and p38 MAPK, were assessed by Western blot. The phosphorylated/active form of STAT3 was decreased in mutant mouse hearts compared with WT in both sexes but was especially noted in female KO hearts (Fig. 3). Additionally, EC STAT3 deficiency also resulted in increased activation of myocardial p38 MAPK. Although seen in both sexes, this observation was particularly noted in female STAT3KO hearts (Fig. 4).


Figure 3
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  		Fig. 3. Expression of activated STAT3 and total STAT3 in myocardial response to I/R in both sexes. Top: representative immunoblots of phosphorylated STAT3 and nonphosphorylated STAT3 are shown (3 lanes/group are shown). Bottom: densitometry data resprented as %phosphorylated (p-)STAT3 vs. total STAT3. Results are means ± SE.

 

Figure 4
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  		Fig. 4. Expression of activated p38 MAPK and total p38 MAPK in myocardial response to I/R in both sexes. Top: representative immunoblots are shown (2 lanes/group are shown). Bottom: bar graph demonstrating relative level of p-p38 vs. p38 MAPK. Results are means ± SE.

 
Effect of STAT3 on myocardial apoptotic signaling following I/R. To elucidate the possible mechanisms that could be involved in I/R-induced myocardial dysfunction in STAT3KO heart, we assessed the effect of STAT3 on myocardial apoptotic signaling. After I/R, increased caspase-8 protein level was observed in STAT3KO heart compared with WT in both sexes (Fig. 5).


Figure 5
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  		Fig. 5. Expression of myocardial caspase-8 after ischemia and reperfusion in both sexes. Top: immunoblots of caspase-8 and GAPDH from WT and STAT3KO heart subjected to I/R (3 lanes/group are shown). Bottom: densitometry data of caspase-8 vs. GAPDH. Results are means ± SE.

 
Myocardial TNF, IL-1beta, and IL-6 production following I/R. Accumulated evidence has demonstrated that I/R-induced local TNF production contributes to myocardial dysfunction (19, 34). Recently, IL-6 has been shown to worsen myocardial function following trauma-hemorrhage injury (39). Additionally, Dr. Harken's group (3) has indicated that IL-1beta plays a synergistic effect with TNF on cardiac function depression. Therefore, we assessed TNF, IL-1beta, and IL-6 level by ELISA to determine whether EC STAT3 mediated the myocardial proinflammatory cytokines following I/R. EC STAT3 deficiency resulted in increased IL-6 production in male hearts but not in females'. Additionally, EC STAT3KO did not affect production of myocardial TNF and IL-1beta in hearts subjected to I/R (Fig. 6).


Figure 6
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  		Fig. 6. Expression of myocardial TNF (A), IL-1beta (B), and IL-6 (C) following I/R injury in both sexes. *P < 0.05 vs. M WT. Results are means ± SE.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
To our knowledge, this is the first study to show that EC STAT3 plays an important role in the sex differences associated with myocardial response to I/R. Here, we observed that 1) EC STAT3KO impaired postischemic myocardial functional recovery and neutralized sex differences in myocardial function following I/R, which was associated with increased LDH release in KO heart in both sexes; 2) ablation of EC STAT3 decreased activation of myocardial STAT3 and increased myocardial p38 MAPK activation in mice subjected to I/R; and 3) I/R increased apoptotic signaling as evaluated by increased expression of caspase-8 in STAT3KO hearts from both sexes.

Myocardial ischemia is a leading cause of heart failure and death in both men and women. Restoration of blood flow to ischemic myocardium results in the I/R injury. The effectiveness of reperfusion therapy is limited by I/R injury in patients with acute surgical ischemia and acute myocardial infarction. Although many scientists have devoted themselves to finding a way to protect ischemic myocardium during reperfusion (23, 32), limited success has been achieved due to our incomplete understanding of the cellular and molecular events that modulate the severity of myocardial I/R injury. Among these, sex appears to play an important role in the myocardial response to ischemia, given that, clinically, women have lower overall incidence of heart failure, slower heart failure progression, better age-matched cardiac contractility than men, and better preservation of myocardial mass as they age (31). Moreover, population studies indicate that males have higher mortality before reaching the hospital after a myocardial infarction (31). In addition, our previous animal studies have demonstrated that females have a better myocardial functional recovery, decreased proinflammatory cytokine production, and reduced apoptotic signaling following I/R (33, 36). Herein, once again we have confirmed that sex differences exist in myocardial function, and better postischemic functional recovery was noticed in female WT hearts compared with males, which was associated with decreased myocardial IL-1beta and IL-6 levels in female WT hearts. However, it is still unclear what specific cellular and molecular events are involved in sex-related differences in myocardial response to I/R.

Recently, our group has demonstrated that sex differences in myocardial function may be attributed to TNFR1 signaling resistance in the female myocardium subjected to acute I/R. This conclusion was further supported after we observed that TNFR1 deficiency resulted in decreased activation of myocardial p38 MAPK and reduced expression of IL-1beta and IL-6 in male hearts, but not in females. Additionally, we have indicated that sex-specific differences existed in myocardial expression of SOCS-3 in response to I/R, with higher levels of SOCS-3 being observed in female hearts than in males'. Furthermore, ablation of TNFR1 resulted in increased SOCS-3 in male hearts but not females’ (35). Given that SOCS-3 is mediated through the STAT3 pathway (9, 40), one may assume that differences in STAT3 signaling may result in TNFR1 pathway resistance in female hearts subjected to I/R.

Indeed, accumulated evidence has indicated that STAT3 exerts protection on the myocardial response to various insults (10, 12). It has been reported that STAT3 can be activated by I/R injury. Activated STAT3 protects the myocardium from ischemic injury via upregulation of antiapoptotic signals (2, 28) or inhibition of antiangiogenic factors and promotion of myocardial capillary formation (11). In this study, impaired myocardial functional recovery with decreased activation of myocardial STAT3 in both sexes is in line with previous observations. In addition, it is not surprising that increased activation of myocardial p38 MAPK has been observed in STAT3KO mice in both sexes, given that myocardial p38 MAPK activation plays a deleterious role in ischemic myocardium (4, 15, 16, 18, 26, 29). This result implies that STAT3 in endothelial cells exerts an indirect effect in the regulation of p38 activation in cardiac myocytes. Furthermore, STAT3 has been reported to transduce antiapoptotic signals in the myocardial response to multiple insults. Cardiomyocyte-restricted KO of STAT3 results in an increased apoptotic response to acute myocardial infarction (11). Furthermore, inhibition of STAT3 activation increases caspase-3 activity and cardiac myocyte apoptosis in hearts subjected to I/R (22). Treatment with LPS enhances myocardial apoptosis in STAT3KO mice (13). In the present study, our experimental period is too brief (20 min of global ischemia followed by 60 min of reperfusion) to detect significant apoptosis in the heart. However, increased apoptotic signals, such as increased expression of caspase-8 and increased myocardial LDH release, have been observed in STAT3KO mice in both sexes after I/R. These results suggest that more damaged cells are present in the STAT3KO myocardium subjected to I/R, which likely correlates with increased myocardial dysfunction in KO mice in both sexes.

STAT3 has also been reported to be a direct target gene for estradiol. Long-term estradiol treatment induces STAT3 activation in mouse liver (8). Additionally, 17beta-estradiol has been shown to affect the immune response via activation of STAT3 and STAT5 in mussel hemocytes (5). In endothelial cells, STAT3 is activated by the addition of 17beta-estradiol and plays a role in conveying nongenomic effects of estrogen (1). Conversely, activated STAT3 has been observed to enhance the transactivation of estrogen receptor (17, 27). Taken together, it becomes clear that cross talk exists between STAT3 and estrogen signaling. Therefore, it can be postulated that females have higher levels of myocardial STAT3 activation than males, which may protect female hearts from ischemia/infarction. Our previous results of increased activation of myocardial STAT3 in female WT compared with males supports this viewpoint. However, in this study we did not observe this phenomenon. The reason might be that mice of different ages were used in these two studies: 16 ± 2-wk-old C57BL mice in the previous study and 4- to 6-wk-old mice in the present study. It would not be surprising that lower levels of estrogen are present in younger female mice.

Here, EC STAT3KO resulted in impaired myocardial contractility and compliance following I/R. Decreased functional recovery was associated with decreased myocardial STAT3 activation and increased p38 MAPK activation, which was more prominent in female hearts than in males'. However, it is unclear how EC STAT3 ablation mediates postischemic myocardial signaling. Given that STAT3-controlled production of local factors from cardiomyocytes has been observed to directly mediate the phenotype of endothelial cells (11), it is in turn proposed that STAT3-mediated paracrine factor production by endothelial cells may affect cardiomyocyte function (Fig. 7). These results provide new evidence for the cross talk among STAT3, TNFR1, and estrogen signaling in the myocardium subjected to I/R. However, these detailed mechanisms require further investigation.


Figure 7
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  		Fig. 7. Simplified pathways illustrating how the endothelial cell STAT3 deficiency affects myocardial STAT3 and p38 MAPK pathway in response to I/R.

 

   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported in part by National Institutes of Health Grants R01-GM-070628 (D. R. Meldrum) and K99-HL-087607-01 (M. Wang), AHA Postdoctoral Fellowship 0526008Z (M. Wang), and an AHA grant-in-aid (D. R. Meldrum). This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program Grant No. C06-RR-015481-01 from the National Center for Research Resources, National Institutes of Health.


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. R. Meldrum, 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.


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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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T. A. Markel, M. Wang, P. R. Crisostomo, M. C. Manukyan, J. A. Poynter, and D. R. Meldrum
Neonatal stem cells exhibit specific characteristics in function, proliferation, and cellular signaling that distinguish them from their adult counterparts
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2008; 294(5): R1491 - R1497.
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