Combined Effects of 17β-estradiol and Exercise Training on Cardiac Apoptosis in Ovariectomized Rats

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Title:	Combined Effects of 17β-estradiol and Exercise Training on Cardiac Apoptosis in Ovariectomized Rats
Authors:	林懿苑;Lin;Yi-Yuan;陳卓昇;Chen, Jwo-Sheng;吳緒波;Wu, Xu-Bo;徐偉成;Cha, Rungchai;Chaunchaiyakul, Rungchai;任曉莉;Zhao, Xian-Li;郭家驊;Kuo, Chia-Hua;鄭宇容;楊艾倫;Yang, Ai-Lun;李信達;Lee, Shin-Da
Contributors:	生物科技學系
Date:	2018-12
Issue Date:	2019-09-10 05:26:48 (UTC+0)
Abstract:	Background The purpose of this study was to investigate the combined 17β-estradiol (E2) and exercise training on cardiac pro-survival and anti-apoptotic pathways in ovariectomized rats. Methods Fifty-six female Sprague–Dawley rats were divided into a sham-operated (Sham), a bilaterally ovariectomized (OVX), an OVX treated with E2 (OVX-E2; 10μg/kg/day), and an OVX with E2 and treadmill exercise training (OVX-E2-EX; 60 min/day, 5 days/week) for 10 weeks. Following 10 weeks of exercise training, rat hearts were isolated for the evaluation of Histopathological analysis, TUNEL assay, and Western blotting. Results The protein levels of estrogen receptor α (ERα), estrogen receptor β (ERβ), insulin-like growth factor 1 (IGF-1), IGF-1 receptor (IGF-1R), phospho-phosphatidylinositol 3-kinase (p-PI3K) (estrogen receptors/IGF-1-related survival pathway) were significantly increased in either the OVX-E2 or OVX-E2-EX group when compared with the OVX group. The protein levels of B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra-large (Bcl-xL) and phosphorylated-Bad (p-Bad) (Bcl-2 family survival pathway) were significantly increased in the OVX-E2-EX group when compared with the OVX group. Only the p-Bad was significantly increased in the OVX-E2 group when compared with the OVX group. PLoS ONE Public Library of Science Combined effects of 17β-estradiol and exercise training on cardiac apoptosis in ovariectomized rats Yi-Yuan Lin, Data curation, Formal analysis, Investigation, Methodology, Jwo-Sheng Chen, Data curation, Formal analysis, Investigation, [...], and Shin-Da Lee, Conceptualization, Project administration, Supervision, Writing – original draft, Writing – review & editing Additional article information Associated Data Data Availability Statement Abstract Background The purpose of this study was to investigate the combined 17β-estradiol (E2) and exercise training on cardiac pro-survival and anti-apoptotic pathways in ovariectomized rats. Methods Fifty-six female Sprague–Dawley rats were divided into a sham-operated (Sham), a bilaterally ovariectomized (OVX), an OVX treated with E2 (OVX-E2; 10μg/kg/day), and an OVX with E2 and treadmill exercise training (OVX-E2-EX; 60 min/day, 5 days/week) for 10 weeks. Following 10 weeks of exercise training, rat hearts were isolated for the evaluation of Histopathological analysis, TUNEL assay, and Western blotting. Results The protein levels of estrogen receptor α (ERα), estrogen receptor β (ERβ), insulin-like growth factor 1 (IGF-1), IGF-1 receptor (IGF-1R), phospho-phosphatidylinositol 3-kinase (p-PI3K) (estrogen receptors/IGF-1-related survival pathway) were significantly increased in either the OVX-E2 or OVX-E2-EX group when compared with the OVX group. The protein levels of B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra-large (Bcl-xL) and phosphorylated-Bad (p-Bad) (Bcl-2 family survival pathway) were significantly increased in the OVX-E2-EX group when compared with the OVX group. Only the p-Bad was significantly increased in the OVX-E2 group when compared with the OVX group. The protein levels of truncation of Bid (t-Bid), Bcl-2-associated death promotor (Bad), Bcl-2-associated X protein (Bax), Cytochrome c, caspases-9, and caspases-3 (mitochondria-dependent apoptotic pathway), as well as the protein levels of tumor necrosis factor-α (TNF-α), Fas ligand, Fas receptors, Fas-associated death domain (FADD), activated caspase-8 and activated caspase-3 (Fas receptor–dependent apoptotic pathway) were significantly decreased in either the OVX-E2 or OVX-E2-EX group when compared with the OVX group. Furthermore, when compared with the OVX-E2 group, the protein levels of ERβ, IGF-1, IGF-1R, Bcl-2 and Bcl-xL were further enhanced in the OVX-E2-EX group as well as the protein levels of Cytochrome c, Fas receptors, FADD, activated caspase-8, activated caspase-9 and activated caspase-3 were further decreased in the OVX-EX-E2 group. Conclusions Combined E2 and exercise training exhibited a positive effect of protection on ovariectomy-induced cardiac apoptosis by enhancing ERβ-related survival pathways, which might provide a more effective therapeutic effect on cardiac protection in bilaterally oophorectomized or menopausal women than E2 treatment only. Introduction According to findings which indicated that women who enter menopause early may be have a higher risk for cardiovascular disease and premature death [1]. Estrogen deficiency at menopause could cause left ventricular hypertrophy and systolic dysfunction, which have been associated with increased cardiac apoptosis, as well as potentially develop heart failure [2, 3]. The cardiomyocyte apoptosis is one of very critical pathological mechanisms to cause heart failure, which can be regarded as marker of poor cardiovascular outcomes [4, 5]. The apoptotic cascade is triggered mitochondria-dependent (intrinsic) and Fas receptor-dependent (extrinsic) apoptotic pathways [6]. The mitochondria-dependent apoptotic pathway is initiated from truncation of Bid (t-Bid) induce the oligomerization of Bcl-2-associated X protein (Bax) and Bcl-2-associated death promotor (Bad). These pro-apoptotic proteins (t-Bid, Bax, and Bad) can enhance release of Cytochrome c into the cytosol, which is responsible for the activation of caspases-9 and caspases-3 [6, 7]. Pathways initiated from the Fas ligand and tumor necrosis factor alpha (TNF-α) binding stimulates trapping of the Fas-receptors, starting with the recruitment of a death-inducing signaling complex (DISC) via Fas-associated death domain (FADD), which is responsible for the activation of caspases-8 and leads to caspase-3 cleavage and executes the cell death program [6]. Our previous studies showed that cardiac Fas-dependent and mitochondria-dependent apoptosis were acticated after ovariectomy [8]. Estrogen not only acts through estrogen receptors (ERα and ERβ), but can also bind to membrane-bound receptors that can cause some of the effects reported [9]. Estrogen is able to mediate stimulation of the IGF-1 receptor (IGF-1R) pathway and phosphorylate IGF-1 receptor (pIGF-1R) [10]. IGF-1 signaling contributes to regulating cardiomyocyte survival through PI3K and Akt activity, which indirectly enhances the Bcl-2 anti-apoptotic family B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra-large (Bcl-xL) and phosphorylated-Bad (p-Bad), and prevents apoptosis [11]. Furthermore, 17β-estradiol (E2) has been shown to suppress cardiac apoptosis through activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway during myocardial infarction [12] E2 is the most abundant ovarian estrogen and may provide cardiovascular protection [13]. A previous study showed that E2 has an anti-apoptotic effect in rat models of myocardial infarction [12]. Moreover, E2 treatment has been shown to attenuate cardiac apoptosis, cardiac remodeling and reducing interstitial myocardial fibrosis after an ovariectomy or aging-related defects [14, 15]. Nevertheless, several research suggested that long-term E2 therapy is associated with an increased risk of breast cancer, or severe menopausal side effects in some women [16, 17]. Physical exercise is a well-known approach for the prevention and treatment of cardiovascular diseases in cardiac rehabilitation [18, 19], and aerobic exercise training has benefits for cardiovascular adaptation in postmenopausal women [20–22]. Our previous study reported that exercise training can significantly prevent cardiac apoptosis in ovariectomized rats [23]. Furthermore, physical activity can also lower the risk of developing breast cancer [24]. However, the combined effect of E2 treatment and exercise training on cardiac apoptosis in early oophorectomized or postmenopausal women is unclear. We hypothesize that the combined effects of E2 treatment and exercise training might have positive effect and more effective than E2 treatment only in preventing mitochondria-dependent and Fas receptor-dependent apoptotic pathways.
Relation:	PLoS One
Appears in Collections:	[Department of Biotechnology] Journal Article

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