Combined effects of 17β-estradiol and exercise training on cardiac apoptosis in ovariectomized rats.

Yi-Yuan Lin,Jwo-Sheng Chen,Rungchai Chaunchaiyakul,Woei-Cherng Shyu,Xian-Li Zhao,Chia-Hua Kuo,Ai-Lun Yang,Shin-Da Lee,Yu-Jung Cheng,Xu-Bo Wu,Yi-Hsien Hsieh

doi:10.1371/journal.pone.0208633

Yi-Yuan Lin, Jwo-Sheng Chen + Show 9 more

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https://doi.org/10.1371/journal.pone.0208633

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Abstract

BackgroundThe 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.MethodsFifty-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.ResultsThe 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.ConclusionsCombined 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.

Highlights

According to findings which indicated that women who enter menopause early may be have a higher risk for cardiovascular disease and premature death [1]
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 were significantly increased in either the OVX treated with E2 (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-Bcl-2-associated death promotor (Bad) (p-Bad) (Bcl-2 family survival pathway) were significantly increased in the OVXE2-EX group when compared with the OVX group

Summary

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 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]. 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

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