E2/ER β Enhances Calcineurin Protein Degradation and PI3K/Akt/MDM2 Signal Transduction to Inhibit ISO-Induced Myocardial Cell Apoptosis

Lin, Kuan Ho; Kuo, Wei Wen; Shibu, Marthandam Asokan; Day, Cecilia Hsuan; Hsieh, You Liang; Chung, Li; Chen, Ray Jade; Su, Wen; Viswanadha, Vijaya Padma; Huang, Chih‐Yang

doi:10.3390/ijms18040892

Cited by 18 publications

(11 citation statements)

References 64 publications

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“…CaMKII is involved in cardiac hypertrophy and apoptosis induced by Iso and testosterone ( Bin-Dayel et al, 2016 ; Duran et al, 2017 ; Park et al, 2018 ), and at the epigenetic level, CaMKII inactivates the negative regulator of adverse cardiac remodeling histone deacetylase 4 (HDAC4), leading to transcriptional activation of the myocyte enhancer factor 2 (MEF2), and phosphorylates histone H3 ( Backs et al, 2009 ; Awad et al, 2013 ). CaN triggers apoptosis and hypertrophy either by dephosphorylating NFAT to activate the subsequent transcription of apoptosis and hypertrophy genes or by dephosphorylating Bad and thereby facilitating the binding of Bad to anti-apoptotic proteins ( Lu et al, 2014 ; Lin et al, 2017 ). The current study showed that upregulation of CaSR was accompanied by increased CaMKII and CaN expression and NFAT-3 nuclear translocation induced by Iso or GdCl 3 .…”

Section: Discussionmentioning

confidence: 99%

Calcium Sensing Receptor-Related Pathway Contributes to Cardiac Injury and the Mechanism of Astragaloside IV on Cardioprotection

Lü

Leng

He³

et al. 2018

Front. Pharmacol.

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Activation of calcium sensing receptor (CaSR) contributes to cardiac injury, but the underlying mechanism has not yet been examined. Astragaloside IV (AsIV) was previously reported to exhibit protective effects against various myocardial injuries. The aim of the present study was to investigate the underlying mechanism of CaSR in cardiac hypertrophy and apoptosis and to evaluate whether the protective effect of AsIV against myocardial injury is associated with CaSR and its related signaling pathway. In vivo and in vitro myocardial injury was induced by isoproterenol (Iso) or GdCl3 (a CaSR agonist) in rats and heart H9C2 cells. Cardiac cell hypertrophy, apoptosis, function, Mitochondrial Membrane Potential (MMP), mitochondrial ultrastructure, and [Ca2+]i, as well as the protein expression of CaSR, calcium/calmodulin-dependent protein kinase II (CaMKII), calcineurin (CaN), sarcoplasmic reticulum Ca2+-ATPase2a (SERCA2a), and the inositol 1,4,5-trisphosphate receptor (IP3R), were measured in vivo and/or in vitro. The results showed that AsIV attenuated cardiac hypertrophy and apoptosis and attenuated impairments in cardiac function, mitochondrial structure, and MMP induced by Iso or GdCl3 in rat myocardial tissue and H9C2 cells. Importantly, AsIV treatment inhibited the enhancement of [Ca2+]i and CaSR expression induced by Iso or GdCl3, an effect similar to that of the CaSR antagonist NPS2143. In addition, AsIV treatment repressed CaSR, CaMKII, and CaN activation and inhibited NFAT-3 nuclear translocation. Mechanistic analysis using lentivirus infection showed that CaSR overexpression activated the CaMKII and CaN signaling pathways and that this response was enhanced by Iso. The results suggested that CaSR-mediated changes in [Ca2+]i and CaMKII and CaN signaling pathways contribute to cardiac hypertrophy and apoptosis and are involved in the protective effect of astragaloside IV against cardiac injury.

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Section: Discussionmentioning

confidence: 99%

Calcium Sensing Receptor-Related Pathway Contributes to Cardiac Injury and the Mechanism of Astragaloside IV on Cardioprotection

Lü

Leng

He³

et al. 2018

Front. Pharmacol.

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“…PLB is phosphorylated by PKA/CaMKII and dephosphorylated by PP1/PP2B. In its phosphorylated form, PLB increases the activity of SERCA2a (31,61,71), whereas its dephosphorylated form inhibits SERCA2a activity (65,79). Numerous studies have shown that long-term estrogen deficiency suppresses SERCA2a expression and activity.…”

Section: Estrogen Regulates Sarco(endo)plasmic Reticulum Ca 2ϩ -Atpasementioning

confidence: 99%

Estrogen and calcium handling proteins: new discoveries and mechanisms in cardiovascular diseases

Jiao

Machuki

et al. 2020

American Journal of Physiology-Heart and Circulatory Physiology

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Estrogen deficiency is considered to be an important factor leading to cardiovascular diseases (CVDs). Indeed, the prevalence of CVDs in postmenopausal women exceeds that of premenopausal women and men of the same age. Recent research findings provide evidence that estrogen plays a pivotal role in the regulation of calcium homeostasis and therefore fine-tunes normal cardiomyocyte contraction and relaxation processes. Disruption of calcium homeostasis is closely associated with the pathological mechanism of CVDs. Thus, this paper maps out and summarizes the effects and mechanisms of estrogen on calcium handling proteins in cardiac myocytes, including L-type Ca2+ channel, the sarcoplasmic reticulum Ca2+ release channel named ryanodine receptor, sarco(endo)plasmic reticulum Ca2+-ATPase, and sodium-calcium exchanger. In so doing, we provide theoretical and experimental evidence for the successful design of estrogen-based prevention and treatment therapies for CVDs.

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“…Xu et al reported that suppression of ovarian hormones increased left ventricle LV) remodeling in rats of advanced age; however, the remodeling could be attenuated by estrogen replacement [ 34 ]. Many studies have reported that the female sex hormone estrogen (E2) and its receptor ERβ play cytoprotective roles in the heart [ 35 , 36 , 37 , 38 , 39 , 40 ]. However, since ERα and ERβ are known to undertake opposing effects, it is important to check the effects of ERα in hypoxia-associated damages [ 41 ].…”

Section: Introductionmentioning

confidence: 99%

Estrogen and/or Estrogen Receptor α Inhibits BNIP3-Induced Apoptosis and Autophagy in H9c2 Cardiomyoblast Cells

Chen

Weng

Shibu

et al. 2018

IJMS

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The process of autophagy in heart cells maintains homeostasis during cellular stress such as hypoxia by removing aggregated proteins and damaged organelles and thereby protects the heart during the times of starvation and ischemia. However, autophagy can lead to substantial cell death under certain circumstances. BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), a hypoxia-induced marker, has been shown to induce both autophagy and apoptosis. A BNIP3-docked organelle, e.g., mitochondria, also determines whether autophagy or apoptosis will take place. Estrogen (E2) and estrogen receptor (ER) alpha (ERα) have been shown to protect the heart against mitochondria-dependent apoptosis. The aim of the present study is to investigate the mechanisms by which ERα regulates BNIP3-induced apoptosis and autophagy, which is associated with hypoxic injury, in cardiomyoblast cells. An in vitro model to mimic hypoxic injury in the heart by engineering H9c2 cardiomyoblast cells to overexpress BNIP3 was established. Further, the effects of E2 and ERα in BNIP3-induced apoptosis and autophagy were determined in BNIP3 expressing H9c2 cells. Results from TUNEL assay and Immunoflourecense assay for LC3 puncta formation, respectively, revealed that ERα/E2 suppresses BNIP3-induced apoptosis and autophagy. The Western blot analysis showed ERα/E2 decreases the protein levels of caspase 3 (apoptotic marker), Atg5, and LC3-II (autophagic markers). Co-immunoprecipitation of BNIP3 and immunoblotting of Bcl-2 and Rheb showed that ERα reduced the interaction between BNIP3 and Bcl-2 or Rheb. The results confirm that ERα binds to BNIP3 causing a reduction in the levels of functional BNIP3 and thereby inhibits cellular apoptosis and autophagy. In addition, ERα attenuated the activity of the BNIP3 promoter by binding to SP-1 or NFκB sites.

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E2/ER β Enhances Calcineurin Protein Degradation and PI3K/Akt/MDM2 Signal Transduction to Inhibit ISO-Induced Myocardial Cell Apoptosis

Cited by 18 publications

References 64 publications

Calcium Sensing Receptor-Related Pathway Contributes to Cardiac Injury and the Mechanism of Astragaloside IV on Cardioprotection

Calcium Sensing Receptor-Related Pathway Contributes to Cardiac Injury and the Mechanism of Astragaloside IV on Cardioprotection

Estrogen and calcium handling proteins: new discoveries and mechanisms in cardiovascular diseases

Estrogen and/or Estrogen Receptor α Inhibits BNIP3-Induced Apoptosis and Autophagy in H9c2 Cardiomyoblast Cells

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