Akt mediates 17β‐estradiol and/or estrogen receptor‐α inhibition of LPS‐induced tumor necresis factor‐α expression and myocardial cell apoptosis by suppressing the JNK1/2‐NFκB pathway

Abstract

Evidence shows that women have lower tumour necrosis factor-α (TNF-α) levels and lower incidences of heart dysfunction and sepsis-related morbidity and mortality. To identify the cardioprotective effects and precise cellular/molecular mechanisms behind estrogen and estrogen receptors (ERs), we investigated the effects of 17β-estradiol (E2) and estrogen receptor α (ERα) on LPS-induced apoptosis by analyzing the activation of survival and death signalling pathways in doxycycline (Dox)-inducible Tet-On/ERα H9c2 myocardial cells and ERα-transfected primary cardiomyocytes overexpressing ERα. We found that LPS challenge activated JNK1/2, and then induced IκB degradation, NFκB activation, TNF-α up-regulation and subsequent myocardial apoptotic responses. In addition, treatments involving E2, membrane-impermeable BSA-E2 and/or Dox, which induces ERα overexpression, significantly inhibited LPS-induced apoptosis by suppressing LPS-up-regulated JNK1/2 activity, IκB degradation, NFκB activation and pro-apoptotic proteins (e.g. TNF-α, active caspases-8, t-Bid, Bax, released cytochrome c, active caspase-9, active caspase-3) in myocardial cells. However, the cardioprotective properties of E2, BSA-E2 and ERα overexpression to inhibit LPS-induced apoptosis and promote cell survival were attenuated by applying LY294002 (PI3K inhibitor) and PI3K siRNA. These findings suggest that E2, BSA-E2 and ERα expression exert their cardioprotective effects by inhibiting JNK1/2-mediated LPS-induced TNF-α expression and cardiomyocyte apoptosis through activation of Akt.

The response of the innate immune and cardiovascular systems to LPS in pregnant and nonpregnant mice†

“…We found no evidence of a differential activation of inflammatory transcription factors and although estradiol has been shown to inhibit the NFκB response in cardiac myocytes in vitro LPS [39], this would not explain the lack of NFκB activation in the NP mice. However, as our earliest time point was 6 h after LPS, any transcription factor may have been missed.…”

17β-Estradiol and/or Estrogen Receptor β Attenuate the Autophagic and Apoptotic Effects Induced by Prolonged Hypoxia Through HIF-1α-Mediated BNIP3 and IGFBP-3 Signaling Blockage

“…We have previously demonstrated that 17β-estradiol and/or ERα exert cardioprotective effects by suppressing JNK1/2-NFκB-mediated LPS-induced TNFα expression and cardiomyocyte apoptosis via Akt activation [16]. Further unpublished studies in our lab also indicate that E2 and/or ERα could act against protein phosphatase 2A (PP2A)-induced cardiac hypertrophy and BNIP3-induced cardiac autophagy and apoptosis.…”

“…More studies have identified that ERα specifically mediate the E2 induced activation of PI3K/Akt signaling pathway in vascular endothelial cells [22][23][24]. Our laboratory previously emphasized that E2 and ERα induce specific Akt and ERK1/2 phosphorylation [16]. In the present study, we focused on the question whether ERβ is also involved in the PI3K/Akt survival pathway.…”

“…However, results from the Women's Health Initiative suggest that estrogen therapy used in post-menopausal females has no beneficial impact against the development of cardiomyopathy such as arteriosclerotic coronary artery disease and myocardial infarction [34]. The controversy may be explained by the findings that estrogen prevents the development of early atherosclerotic lesions by reducing lipid deposits when hormone therapy is initiated in the premenopausal period or before the development of atherosclerosis [16]. However, estrogen can promote MMP expression, inflammatory activation and plaque instability once atherosclerosis has been established [34].…”

Gender and the Pathogenesis of Gastrointestinal Diseases: The Role of Steroid Sex Hormones in the Development

“…Vascularsmooth muscle and endothelial cells have been reported to express ERα and Erβ protein & mRNA [34][35][36]. Oestrogen has been proved to have anti-inflammatory effect by acting against inflammatory promoters, such as bacterial cell wall component, lipopolysaccharide (LPS) via activating ERα [37][38][39][40][41][42].…”