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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 41  |  Issue : 3  |  Page : 146-152

Estrogen deficiency accompanied by oxidative stress sustains heme oxygenase 1 expression in cardiomyocytes of ovariectomized rats


1 Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan
2 Department of Surgery, Division of Cardiovascular Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
3 Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan
4 Department and Graduate Institute of Pharmacology; Department of Pharmacy Practice, Tri-Service General Hospital, National Defense National Defense Medical Center, Taipei, Taiwan

Date of Submission09-Jun-2020
Date of Decision04-Aug-2020
Date of Acceptance20-Aug-2020
Date of Web Publication06-Oct-2020

Correspondence Address:
Dr. Hsin-Hsueh Shen
Department and Graduate Institute of Pharmacology, National Defense Medical Center, No. 161, Section 6, Min-Chuan East Road, Taipei 114
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmedsci.jmedsci_175_20

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  Abstract 


Background: Estrogen deficiency is one of the main causes of cardiovascular diseases (CVDs) after menopause, accompanied with the upregulation of oxidative stress. Two isoforms of heme oxygenase (HO), HO-1 and HO-2, have been implicated in the cytoprotective effects via the antioxidant and anti-inflammatory capacities. Aims: This study aimed to investigate the time-course of HO-1 and HO-2 expression in the cardiac tissue of ovariectomized rats and whether oxidative stress is involved in the regulation of HO alteration. Methods: Adult female rats were ovariectomized bilaterally to induce estrogen deficiency and randomly divided into (1) Sham, (2) ovariectomy (Ovx), (3) Ovx + E2 (17β estradiol, 50 μg/kg/day, intramuscular), and (4) Ovx + tempol (1 mM in drinking water, a superoxide dismutase [SOD] mimetic). Rats were sacrificed 12 weeks after Ovx; blood and myocardium samples were collected. Results: Showed that plasma E2 levels of Ovx and Ovx + tempol groups were significantly reduced as compared to Sham group after 4 weeks of Ovx. Superoxide anion in the cardiac tissue was significantly elevated 2 weeks after Ovx, and the increase was drastically reversed by the treatment with E2 and tempol. In addition, Ovx rats showed significantly higher levels of oxidized glutathione (GSSG) than those of Sham group, which were also significantly reduced by E2 and tempol administration. Western blot analysis indicated that HO-1 expression was significantly induced 1 week after Ovx and sustained at high levels until 12 weeks. E2 replacement did not immediately reverse HO-1 until treatment for 4 weeks as well as tempol administration for 5 weeks. Expression of the constitutive enzymes HO-2 did not show significant differences between Sham and Ovx groups, and E2 or tempol administration had no effect on cardiac HO-2 protein expression. Conclusion: E2 deficiency induced upregulation of superoxide anion in the myocardium, which might be the major contributor to the sustained HO-1 expression as adaptive responses to oxidative stress. This study provides new insight into the pathogenesis of CVDs after menopause.

Keywords: Heme oxygenase, cardiomyocyte, oxidative stress, estrogen, ovariectomy


How to cite this article:
Lai ZZ, Yang HY, Chen PN, Shih WJ, Shen HH, Lee YM. Estrogen deficiency accompanied by oxidative stress sustains heme oxygenase 1 expression in cardiomyocytes of ovariectomized rats. J Med Sci 2021;41:146-52

How to cite this URL:
Lai ZZ, Yang HY, Chen PN, Shih WJ, Shen HH, Lee YM. Estrogen deficiency accompanied by oxidative stress sustains heme oxygenase 1 expression in cardiomyocytes of ovariectomized rats. J Med Sci [serial online] 2021 [cited 2021 Jun 22];41:146-52. Available from: https://www.jmedscindmc.com/text.asp?2021/41/3/146/297430




  Introduction Top


Premenopausal women are less susceptible to myocardial infarction and cardiovascular diseases (CVDs) than men of the same age, and this advantage disappears after the onset of menopause.[1] Although the pathological mechanisms are similar in CVDs of men and women, gender differences exist in the anatomy and physiology of the myocardium, and sex hormones modify the progress of disease in women.[2] Estrogen deficiency after menopauses causes left ventricular hypertrophy and systolic dysfunction, which have been associated with increased cardiac apoptosis and potentially contribute to the development of heart failure.[3] Moreover, depletion of estrogen augments cardiac inflammation and oxidative stress, which results in aggravation of myocardial fibrosis and diastolic dysfunction in hypertensive female rats.[4] The antioxidant and anti-inflammatory effects of estrogen may play an important role in mediating these cardioprotective effects.[5],[6] Thus, loss of estrogen prompted the imbalance between elevated reactive oxygen species (ROS) production and reduced antioxidant activity.

Heme oxygenase (HO) system plays a critical role in mediating the cytoprotective effects via the antioxidant and anti-inflammatory properties in the cardiovascular system.[7] It is apparent that two functionally isoforms of HO have been discovered in mammals, the inducible HO-1 and the constitutive HO-2. Both isozymes catalyze the rate-limiting step in heme degradation, leading to the formation of biliverdin with the concurrent release of carbon monoxide (CO) and free iron.[8],[9] Biliverdin is reduced enzymatically to bilirubin, which is a potent endogenous scavenger of ROS. Moreover, CO exerts anti-apoptotic and anti-inflammatory as well as vasodilatory effects through the induction of soluble guanylyl cyclase.[10] HO-1 is induced by a variety of compounds and generally considered as the first-line defense mechanism against oxidative stress.[9] Upregulation of HO-1 has now been described in diverse oxidative stress-mediated vascular diseases. Recent data support the involvement of HO system in the antioxidant and anti-inflammation effects, which is closely regulated by estrogen.[8]

Ovariectomy (Ovx) has been widely used to mimic estrogen deficiency in experimental model of menopause.[11],[12] We have previously shown that oxidative stress resulting from E2 depletion caused by Ovx induced HO-1 expression in the aorta to modulate the cytoprotective effects.[13] However, the underlying mechanisms in the cardiomyocytes are not fully understood. The present study aimed to investigate the time-course changes of HO-1 and HO-2 expression in the myocardial tissues of ovariectomized rats and whether oxidative stress is involved in the alteration of HO caused by estrogen deprivation.


  Methods Top


Animal preparation

Female Sprague–Dawley rats (8 weeks old, 250–380 g) were purchased from National Laboratory Animal Breeding and Research Center of Ministry of Science and Technology, Taiwan. Handling of the animals was in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85–23, revised in 1996). This study was approved by the Institutional Animal Care and Use Committee of the National Defense Medical Center, Taiwan (Number of Permission: IACUC-03-068, May 2, 2003). All animals were housed at an ambient temperature of 22°C ± 1°C and humidity of 55% ± 5%.

To generate a model with particular emphasis on menopausal phenotypes, we conducted a surgical intervention to produce bilateral OVX. Female rats were anesthetized with sodium pentobarbital (50 mg/kg) by intraperitoneal injection and received bilateral Ovx. Small incisions were made bilaterally on the sides of their backs and exposed the ovaries retroperitoneally. The ovaries were clamped and removed, and the uterine tubes were subsequently ligated. After all the procedure, the muscle and skin were sutured and disinfected with povidone iodine. The sham procedure consisted of anesthesia, incisions of abdominal cavity, visualization of the ovaries and closure of the wounds.

Experimental group

One week after the operation, rats were randomly divided into four groups: (i) Sham group: rats received sham operations (n = 3); (ii) Ovx group: rats were ovariectomized bilaterally (n = 27); (iii) Ovx + E2 group: the rats with Ovx were intramuscularly injected with 17-β estradiol (50 μg/kg/day) for 5 weeks beginning at one week after Ovx (n = 15); (iv) Ovx + tempol group: rats with Ovx were administered with tempol (1 mM in drinking water), a membrane–permeable SOD mimetic[14] for 5 weeks beginning at 1 week after Ovx (n = 15).

Plasma E2 assay

Blood samples (1 ml) were withdrawn from the abdominal aorta using heparinized syringes under anesthesia at 6 weeks after Ovx and centrifuged at 4°C for 10 min. Plasma concentration of E2 was determined by 125I radioimmunoassay using a commercially available kit (Diagnostic Products, Los Angeles, CA, USA). The protocol provided by the manufacturer was strictly followed.

Measurement of cardiac superoxide anion formation by chemiluminescence

Superoxide anion production in the cardiomyocytes was measured by lucigenin-enhanced chemiluminescence, as described previously.[15] Briefly, myocardium samples (3 mm × 3 mm) were placed in scintillation plates containing Krebs–2-[4-(2-hydroxyethyl)-ethanesulfonic acid buffer. Lucigenin (1.25 mM) was added into a microplate luminometer (Hidex, Microplate Luminometer, Finland). Counts were obtained in duplicate at a 15-s interval. All the samples were dried in a 90°C oven for 16 h. These results were expressed as count per second per milligram of myocardium dry weight.

Measurements of oxidized glutathione in the myocardium of ovariectomy rats

The levels of oxidized glutathione (GSSG) in the myocardium were considered as a cellular indicator of oxidative stress. The measurement of GSSG levels was performed by the colorimetric assay kit (Oxis International, Portland, OR) according to the manufacturer's instructions.

Western blot analysis of heme oxygenase-1 and heme oxygenase-2 protein expression in the hearts of ovariectomy rats

Total proteins of the myocardium were extracted using radioimmunoprecipation assay lysis buffer within 1% protease inhibitor cocktail (Millipore, Bedford, MA, USA) 0.1 mM according to the manufacturer's instructions. Protein samples were separated using 10% sodium dodecyl sulfate-polyacrylamide gels and transferred to a nitrocellulose membrane (Millipore, Bedford, MA, USA). After blocking, the membranes were then incubated at 4°C overnight with the following primary antibodies: anti-HO-1, anti-HO-2 (1:1000, Cell Signaling Technology, Danvers, MA, USA) and anti-β-actin (1:5000, Cell Signaling). After washing, the membranes were probed with corresponding secondary antibodies (1:3000, Cell Signaling). The density of the individual protein bands was quantified by densitometric scanning of the blots using ImageJ software.

Statistical analysis

Statistical evaluation of others was performed with one-way analysis of variance followed by the Newman–Keuls method. A value of P < 0.05 was accepted as statistical significance.


  Results Top


Plasma E2 concentration

The plasma E2 concentration 5 weeks after Ovx averaged 38.0 ± 10.6 pg/mL, which was significantly lower than that of Sham group (120.8 ± 4.7 pg/mL). Replacement with E2 for 5 weeks (Ovx + E2 group) markedly increased the plasma E2 levels (120.3 ± 20.0 pg/mL) as compared to Ovx group (P < 0.05) but not significantly different from that in the Sham group (P > 0.05). However, plasma E2 levels in the Ovx + T group were 43.8 ± 8.7 pg/mL, which was significantly lower than that of Sham group (P > 0.05) [Figure 1].
Figure 1: Plasma levels of 17β estradiol 5 weeks after ovariectomy in rats. Data are given as mean ± standard deviation error (n = 3). *P < 0.05 versus Sham group; #P < 0.05 versus ovariectomy group

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Superoxide anion formation in the cardiomyocytes of ovariectomy rats

To elucidate the effects of estrogen depletion on oxidative stress in the myocardium of Ovx rats, superoxide anion formation was detected. As shown in [Figure 2], superoxide anion formation in the cardiomyocytes of Ovx group (24.8 ± 2.2 cps/mg) was significantly higher than that of Sham group (12.4 ± 1.4 cps/mg). E2 replacement (11.3 ± 2.8 cps/mg) significantly inhibited the increase of the superoxide anion formation when compared to Ovx group. Similar result was also observed that tempol administration in the Ovx rats (7.1 ± 1.5 cps/mg) significantly diminished the cardiac superoxide formation as compared to Ovx group.
Figure 2: Effects superoxide anion formation in the myocardium 2 weeks after ovariectomy in rats. Data are given as mean ± standard deviation error (n = 3). *P < 0.05 versus Sham group; #P < 0.05 versus ovariectomy group

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Oxidized glutathione formation in the cardiomyocytes of ovariectomy rats

Five weeks after Ovx, the GSSG levels in the hearts of the Ovx rats were 12.9 ± 0.9 nmole/mg, which was significantly higher than those of Sham group (3.6 ± 0.9 nmole/mg). Both replacement with E2 (7.5 ± 0.3 nmol/mg) and chronic treatment with tempol (6.3 ± 0.2 nmol/mg) in the Ovx rats for 5 weeks showed remarkable reduction of GSSG levels when compared to the Ovx group [Figure 3].
Figure 3: Effects of oxidized glutathione (GSSG) in the myocardium 5 weeks after ovariectomy in rats. Data are given as mean ± standard deviation error (n = 3). *P < 0.05 versus Sham group; #P < 0.05 versus ovariectomy group

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Time-course changes of heme oxygenase-1 protein expression in the cardiomyocytes of ovariectomy rats

Western blot analysis was used to investigate the time-course changes of HO-1 protein expression in the cardiomyocytes of Ovx rats. As shown in [Figure 4], HO-1 protein expression was significantly induced 1 week after Ovx as compared to the Sham group (P < 0.05), and the induction of HO-1 sustained at high level until 12 weeks after Ovx, which was significantly increased when compared with Sham group (P < 0.05).
Figure 4: Time-course changes in heme oxygenase 1 protein expression in the myocardium 1–12 weeks after ovariectomy in rats. Data are given as mean ± standard deviation error (n = 3 for each time point). *P < 0.05 versus Sham group; #P < 0.05 versus ovariectomy group

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[Figure 5] shows that after 1–3 weeks of E2 replacement in Ovx rats, the HO-1 protein expression was significantly higher than that of Sham group (P < 0.05). After E2 replacement for 4 weeks, the increase of HO-1 protein was dramatically reversed and lasted until 5 weeks (P < 0.05). Similar results were also observed that treatment with tempol 1–4 weeks in the Ovx rats did not decrease the induction of HO-1 expression. However, after 5 weeks of tempol administration, the HO-1 expression showed drastic reduction and was significantly lower than that of 1-week tempol treatment in the Ovx rats [Figure 6].
Figure 5: Effects of replacement with 17β estradiol on heme oxygenase 1 protein expression in the myocardium of rats with ovariectomy. Data are given as mean ± standard deviation error (n = 3 for each time point). *P < 0.05 versus Sham group; #P < 0.05 versus ovariectomy group. 17β estradiol: 50 μg/kg/day, intramuscular

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Figure 6: Effects of administration with tempol on heme oxygenase 1 protein expression in the myocardium of rats with ovariectomy. Data are given as mean ± standard deviation error (n = 3 for each time point). *P < 0.05 versus Sham group; #P < 0.05 versus ovariectomy group.

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Time-course changes of heme oxygenase-2 protein expression in the cardiomyocytes of ovariectomy rats

We then measured time-course changes of HO-2 protein expression, the constitutive form of HO, and investigated whether estrogen deficiency affected cardiac HO-2 expression in the Ovx rats. As shown in [Figure 7], no significant difference was observed 1–12 weeks after Ovx rats when compared to Sham-operated group [Figure 7]. E2 replacement or tempol administration for 1–5 weeks did not show significant difference of HO-2 protein expression in the cardiomyocytes when compared to the Sham group [Figure 8].
Figure 7: Time-course changes of heme oxygenase-2 protein expression in the cardiomyocytes 1–12 weeks after ovariectomy in rats. Data are given as mean ± standard deviation error (n = 3 for each time point)

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Figure 8: Effects of treatment with 17β estradiol (a) and tempol (b) on heme oxygenase-2 protein expression in the cardiomyocytes of ovariectomy in rats

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  Discussion Top


In the present study, the relationship between the estrogen, oxidative stress, as well as the antioxidant HO system homeostasis has been investigated. Results showed that long-term estrogen deficiency was accompanied with significant increase in superoxide anion formation and GSSG in the cardiomyocytes of Ovx rats. Induction of HO-1 in response to the augmented oxidative stress may exert the cytoprotective capacities in the cardiomyocytes of Ovx rats. Exogenous replacement of E2 and administration with antioxidant tempol diminished the induction of HO-1 in the cardiomyocytes of Ovx rats. In addition, the constitutive HO-2 expression in the heart was not changed by estrogen depletion, whereas E2 replacement as well as tempol treatment has no influence on cardiac HO-2 expression. In conclusion, our results showed the induction of HO-1 in the hearts is an adaptive response to estrogen deficiency-induced oxidative stress and ascertained that HO-1 as a logical target for intervention therapy of CVDs in menopause.

CVDs are the leading cause of morbidity and mortality amid postmenopausal women,[2] and the mechanisms responsible for the increased prevalence of CVDs in postmenopausal women are varied and complicated.[16] Estrogen has a critical role in the preservation of cardiovascular health, and the loss of estrogen associated with menopause increases the risk of CVDs. As previously reported in many studies, ventricular myocytes from young female rats were more resistant to ischemia/reperfusion (IR) injury than those from males, and this protective effects were diminished by Ovx or aging.[17] Intracellular Ca2+ dysregulation in the cardiomyocytes resulting from estrogen depletion may also contribute to the susceptibility of IR injury. Furthermore, we have previously shown that Ovx enhanced the risk of myocardial infarction and the severity of reperfusion injury, whereas replacement with E2 can reduce these damages.[18] The cardioprotective effects of estrogen are mediated through estrogen receptor (ER)-α and ER-β and are both direct and indirect. The direct effect comprises steroid receptors that are capable of altering gene expression to possess cardiovascular protective effects.

A number of studies have demonstrated that oxidative stress contributes to the proliferation, phenotypic transition, and collagen synthesis, which results in cardiac fibrosis and myocardial remodeling.[19] The natural antioxidant effect of estrogen has been widely documented in previous investigation.[20] Estrogen decreased the myocardial infarct size and the incidence of IR injury as well as neutrophil infiltration in the cardiac muscle.[6] The antioxidant property of estrogen protects female against free radicals and oxidative stress damage via upregulation of the SOD[16] and catalase.[21] To verify the antioxidant role of E2 in the cardiomyocytes, GSSG content has been also measured as an indicator of oxidative in the hearts. Our study showed that estrogen deficiency resulted in a significant increase in the level of superoxide anion formation and GSSG in the cardiomyocytes. However, exogenous hormone or antioxidant tempol administration reduced the levels of GSSG. It has been reported that estrogen deficiency induced the downregulation of manganese SOD (MnSOD) and extracellular SOD, which was associated with increased production of ROS,[16] while E2 replacement prevented this change, suggesting the antioxidative properties of E2 to possess cardiovascular protective roles after deprivation of estrogen. In line with these results, the involvement of oxidative stress after estrogen deprivation is the major cause to contribute to the CVDs in the menopausal women.

HO-1 is a 32 kDa microsomal protein (also known as heat shock protein 32) and exerts protective effects from oxidative stress damage in the cardiovascular system. The cytoprotective effects of HO-1 are mediated by its products, CO, biliverdin/bilirubin, and free iron, and we were interested in the time-course changes of this antioxidant protein in the estrogen-deficient condition. It is commonly assumed that HO-1 induction in the myocardium exerts cardioprotective effects such as antioxidant and anti-inflammation. Cardiac-specific HO-1 transgenic overexpression reduced ventricular dilation, fibrosis, and oxidative stress in IR injury, thus improving the recovery of cardiac function.[22] Estrogen promoted the nuclear translocation of nuclear transcription factor Nrf2 and induced HO-1 during the process of H/R injury,[20] further implying the interaction between estrogen and HO-1. In this study, the induction of HO-1 was observed 1 week after Ovx and sustained to 12 weeks accompanied by elevated oxidative stress, indicating that free radicals are an inducer of HO-1 expression in the cardiomyocytes. After E2 replacement for 5 weeks, the induction of HO-1 dramatically disappears. Similar results were also shown in the tempol treatment group of Ovx rats, suggesting that the effect of E2 on HO-1 induction is mainly mediated by its antioxidant capacity. Thus, the induction of HO-1 might be an adaptive response to the augmented oxidative stress during estrogen deficiency and be evident to slow the processes of hypertension and myocardial infarction.[23] However, E2 replacement and antioxidant tempol administration alleviated the high oxidative stress caused by Ovx, resulting in the downregulation of HO-1 in the cardiomyocytes. These results were in accordance with our previous study in the aorta of Ovx rats, revealing that oxidative stress induced vascular HO-1 and inducible NO synthase expression.[13]

HO-2, a 36-kDa protein, is constitutively expressed to maintain cell homeostasis and is altered in pathological conditions.[24] A novel role of HO-2 was reported to be a prerequisite in the regulation of the inflammatory and reparative response to injury, which is crucial for an ordered execution associated with HO-1 induction.[25] Interestingly, we found that HO-2 was not regulated by estrogen in the cardiomyocytes, and these results are in line with previous reports in human neuroblastoma cells to mediate the protective effects.[26]


  Conclusions Top


Our study unravels estrogen deficiency upregulates superoxide anion in the myocardium, which sustains HO-1 expression in response to oxidative stress and provides new insight into the pathogenesis of CVDs after menopause.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Chung MT, Cheng PY, Lam KK, Chen SY, Ting YF, Yen MH, et al. Cardioprotective effects of long-term treatment with raloxifene, a selective estrogen receptor modulator, on myocardial ischemia/reperfusion injury in ovariectomized rats. Menopause 2010;17:127-34.  Back to cited text no. 18
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]



 

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