Non-genomic Effects of Estrogen on Cell Homeostasis and Remodeling With Special Focus on Cardiac Ischemia/Reperfusion Injury

Puglisi, Rossella; Mattia, Gianfranco; Caré, Alessandra; Marano, Giuseppe; Malorni, Walter; Matarrese, Paola

doi:10.3389/fendo.2019.00733

Cited by 40 publications

(42 citation statements)

References 230 publications

(209 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…During estrogen binding with ER, and the heat shock proteins (HSP70 and HSP90) dissociate ER from this binding in the cytosol, and change their conformation, then migrate as dimers into the nucleus to bind with EREs. This conformational change also allows helix 12 (H12) to accept coactivators and activate gene transcription (10,(20)(21)(22)(23)(24).…”

Section: Direct Genomic/classicalmentioning

confidence: 99%

Molecular Mechanisms of Endocrine Resistance in Estrogen-Receptor-Positive Breast Cancer

Belachew

Sewasew

2021

Front. Endocrinol.

View full text Add to dashboard Cite

The estrogen receptor is a vital receptor for therapeutic targets in estrogen receptor-positive breast cancer. The main strategy for the treatment of estrogen receptor-positive breast cancers is blocking the estrogen action on estrogen receptors by endocrine therapy but this can be restricted via endocrine resistance. Endocrine resistance occurs due to both de novo and acquired resistance. This review focuses on the mechanisms of the ligand-dependent and ligand-independent pathways and other coregulators, which are responsible for endocrine resistance. It concludes that combinatorial drugs that target different signaling pathways and coregulatory proteins together with endocrine therapy could be a novel therapeutic modality to stop endocrine resistance.

show abstract

Section: Direct Genomic/classicalmentioning

confidence: 99%

Molecular Mechanisms of Endocrine Resistance in Estrogen-Receptor-Positive Breast Cancer

Belachew

Sewasew

2021

Front. Endocrinol.

View full text Add to dashboard Cite

show abstract

“…The classical genomic pathways involve transcription of prosurvival genes facilitated by estrogen response elements (EREs) (14) and super-enhancers (15). Another genomic signaling is controlled by an indirect nuclear ER binding to DNA that is mediated by cofactors like NF-κB or AP-1 and SP-1 to exert their transcription regulation (16,17). Classic ERs at the plasma membrane and cytosol can also mediate E2 action via non-genomic signaling, including activating kinases or binding to scaffold proteins to modulate multiple prosurvival pathways (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

“…Another genomic signaling is controlled by an indirect nuclear ER binding to DNA that is mediated by cofactors like NF-κB or AP-1 and SP-1 to exert their transcription regulation (16,17). Classic ERs at the plasma membrane and cytosol can also mediate E2 action via non-genomic signaling, including activating kinases or binding to scaffold proteins to modulate multiple prosurvival pathways (17)(18)(19). Besides these effects mediated through its two steroidal ERs, a complementary but separate mode of rapid E2 actions have been reported that depend on agonist activation of the membrane-bound GPER1.…”

Section: Introductionmentioning

confidence: 99%

Chronic GPER1 Activation Protects Against Oxidative Stress-Induced Cardiomyoblast Death via Preservation of Mitochondrial Integrity and Deactivation of Mammalian Sterile-20-Like Kinase/Yes-Associated Protein Pathway

et al. 2020

View full text Add to dashboard Cite

Introduction: Estrogen (17β-estradiol, E2) is well-known to induce cardioprotective effects against ischemia/reperfusion (I/R) injury. We recently reported that acute application of E2 at the onset of reperfusion in vivo induces cardioprotective effects against I/R injury via activation of its non-steroidal receptor, G protein-coupled estrogen receptor 1 (GPER1). Here, we investigated the impact and mechanism underlying chronic GPER1 activation in cultured H9c2 rat cardiomyoblasts. Methods: H9c2 rat cardiomyoblasts were cultured and pretreated with the cytotoxic agent H 2 O 2 for 24 h and incubated in the presence of vehicle (control), GPER1 agonists E2 and G1, or GPER1 agonists supplemented with G15 (GPER1 antagonist) for 48 or 96 h. After treatment, cells were collected to measure the rate of cell death and viability using flow cytometry and Calcein AM assay or MTT assay, respectively. The resistance to opening of the mitochondrial permeability transition pore (mPTP), the mitochondrial membrane potential, and ATP production was assessed using fluorescence microscopy, and the mitochondrial structural integrity was observed with electron microscopy. The levels of the phosphorylation of mammalian sterile-20-like kinase (MST1) and yes-associated protein (YAP) were assessed by Western blot analysis in whole-cell lysate, while the expression levels of mitochondrial biogenesis genes, YAP target genes, and proapoptotic genes were measured by qRT-PCR. Results: We found that after H 2 O 2 treatment, chronic E2/G1 treatment decreased cell death effect was associated with the prevention of the S phase of the cell cycle arrest compared to control. In the mitochondria, chronic E2/G1 activation treatment preserved the cristae morphology, and increased resistance to opening of mPTP, but Imam Aliagan et al. Chronic GPER1 Actions and Cell Death with little change to mitochondrial fusion/fission. Additionally, chronic E2/G1 treatment predominantly reduced phosphorylation of MST1 and YAP, as well as increased MST1 and YAP protein levels. E2 treatment also upregulated the expression levels of TGFβ and PGC-1α mRNAs and downregulated PUMA and Bim mRNAs. Except for ATP production, all the E2 or G1 effects were prevented by the cotreatment with the GPER1 antagonist, G15. Conclusion: Together, these results indicate that chronic GPER1 activation with its agonists E2 or G1 treatment protects H9c2 cardiomyoblasts against oxidative stressinduced cell death and increases cell viability by preserving mitochondrial structure and function as well as delaying the opening of mPTP. These chronic GPER1 effects are associated with the deactivation of the non-canonical MST1/YAP mechanism that leads to genetic upregulation of cell growth genes (CTGF, CYR61, PGC-1α, and ANKRD1), and downregulation of proapoptotic genes (PUMA and Bim).

show abstract

“…It is thus tempting to suggest that this differential modulation of GRK2 might have been caused by the occurrence of the different tissue-specific regulatory mechanisms triggered by ovarian hormones/estrogens which would be dependent on the muscle type. These modulations could potentially occur by way of differential activation of the classical nuclear receptors and/or the cytoplasmic actions of GPER that might mediate both the genomic and non-genomic actions and ultimately impinge upon GRK2 modulation [ 45 , 46 ]. Estrogens have been previously described as upregulating GRK2 levels in the brain [ 47 ] and breast cancer cells [ 48 ], results that are in line with our data concerning the skeletal, but not in the cardiac, muscles.…”

Section: Discussionmentioning

confidence: 99%

Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones

Arcones

Martínez-Cignoni

Vila-Bedmar

et al. 2021

Cells

View full text Add to dashboard Cite

Cardiovascular disease (CVD) risk shows a clear sexual dimorphism with age, with a lower incidence in young women compared to age-matched men. However, this protection is lost after menopause. We demonstrate that sex-biased sensitivity to the development of CVD with age runs in parallel with changes in G protein-coupled receptor kinase 2 (GRK2) protein levels in the murine heart and that mitochondrial fusion markers, related to mitochondrial functionality and cardiac health, inversely correlate with GRK2. Young female mice display lower amounts of cardiac GRK2 protein compared to age-matched males, whereas GRK2 is upregulated with age specifically in female hearts. Such an increase in GRK2 seems to be specific to the cardiac muscle since a different pattern is found in the skeletal muscles of aging females. Changes in the cardiac GRK2 protein do not seem to rely on transcriptional modulation since adrbk1 mRNA does not change with age and no differences are found between sexes. Global changes in proteasomal or autophagic machinery (known regulators of GRK2 dosage) do not seem to correlate with the observed GRK2 dynamics. Interestingly, cardiac GRK2 upregulation in aging females is recapitulated by ovariectomy and can be partially reversed by estrogen supplementation, while this does not occur in the skeletal muscle. Our data indicate an unforeseen role for ovarian hormones in the regulation of GRK2 protein levels in the cardiac muscle which correlates with the sex-dependent dynamics of CVD risk, and might have interesting therapeutic applications, particularly for post-menopausal women.

show abstract

Non-genomic Effects of Estrogen on Cell Homeostasis and Remodeling With Special Focus on Cardiac Ischemia/Reperfusion Injury

Cited by 40 publications

References 230 publications

Molecular Mechanisms of Endocrine Resistance in Estrogen-Receptor-Positive Breast Cancer

Molecular Mechanisms of Endocrine Resistance in Estrogen-Receptor-Positive Breast Cancer

Chronic GPER1 Activation Protects Against Oxidative Stress-Induced Cardiomyoblast Death via Preservation of Mitochondrial Integrity and Deactivation of Mammalian Sterile-20-Like Kinase/Yes-Associated Protein Pathway

Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones

Contact Info

Product

Resources

About