Activation of G protein–coupled estrogen receptor protects intestine from ischemia/reperfusion injury in mice by protecting the crypt cell proliferation

Chai, Shiquan; Liu, Kaixuan; Feng, Wanbing; Liu, Tiantian; Wang, Qian; Zhou, Rong; Chen, Shiming; Wang, Liyan; Chen, Guan-Yu; Tian, Mei; Zhao, Jiandong; Liu, Chuanyong; Xue, Bing

doi:10.1042/cs20180919

Cited by 25 publications

(16 citation statements)

References 70 publications

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“…GPER1 activation is now well-known for inducing protective effects in several disease models, including I/R injury, hypertension (4-6), Parkinson's disease (23), retinal ganglion degeneration (74), and breast cancer (75). In fact, GPER1 activation has been reported to exert protective effects against harmful effects in several other organs, including the heart (4-6), brain (21,76), muscle (77), testes (77), intestine (26), and kidney (78). Using isolated perfused heart model, others and we have reported that acute (∼1 h) pre-ischemic E2 treatment induces cardioprotective effects against I/R injury through GPER1 activation (4)(5)(6)(7)(8).…”

Section: Discussionmentioning

confidence: 99%

“…We also showed that acute GPER1 stimulation during reperfusion elicits cardioprotective effects involving the delay of mitochondrial permeability transition pore (mPTP) opening, reduction of mitochondrial dysfunction, and mitophagy (5,20). In intestinal crypt cells, pre-ischemic GPER1 activation has been suggested to alleviate the injury induced by I/R and improve proliferative ability of crypt stem cell by inhibiting iNOS expression (26).…”

Section: Introductionmentioning

confidence: 93%

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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

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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).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

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

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“…Effects of G-1 in GPER knockout models were negligible (30), suggesting that G-1 is a specific agonist of GPER. In a mouse model of ischemia-reperfusion injury, G-1 significantly improved intestinal mucosal damage and alleviated neutrophil infiltration (31). Interestingly, an increase of E2 and G1 sensitivity in tamoxifen-resistant MCF-7 cells has been reported (32).…”

Section: Gper Agonism and Antagonismmentioning

confidence: 99%

G Protein-Coupled Estrogen Receptor: A Potential Therapeutic Target in Cancer

Yu²,

Dong

et al. 2019

Front. Endocrinol.

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The G protein-coupled estrogen receptor (GPER) is a seven-transmembrane-domain receptor that mediates non-genomic estrogen related signaling. After ligand activation, GPER triggers multiple downstream pathways that exert diverse biological effects on the regulation of cell growth, migration and programmed cell death in a variety of tissues. A significant correlation between GPER and the progression of multiple cancers has likewise been reported. Therefore, a better understanding of the role GPER plays in cancer biology may lead to the identification of novel therapeutic targets, especially among estrogen-related cancers. Here, we review cell signaling and detail the functions of GPER in malignancies.

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“…Our previous studies showed that GPER in jejunum crypts had a protective effect on the proliferation of crypt cells after injury [ 28 ]. Here, we found the reduction of BrdU + (marking S phase cells) and Ki67 + cells (marking proliferating cells) in the crypts induced by 5-FU was corrected by G-1 treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

Activation of G protein coupled estrogen receptor prevents chemotherapy-induced intestinal mucositis by inhibiting the DNA damage in crypt cell in an extracellular signal-regulated kinase 1- and 2- dependent manner

Chen

Zeng

et al. 2021

Cell Death Dis

Self Cite

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Chemotherapy-induced intestinal mucositis (CIM) is a common adverse reaction to antineoplastic treatment with few appropriate, specific interventions. We aimed to identify the role of the G protein coupled estrogen receptor (GPER) in CIM and its mechanism. Adult male C57BL/6 mice were intraperitoneally injected with 5-fluorouracil to establish the CIM model. The selective GPER agonist G-1 significantly inhibited weight loss and histological damage in CIM mice and restored mucosal barrier dysfunction, including improving the expression of ZO-1, increasing the number of goblet cells, and decreasing mucosal permeability. Moreover, G-1 treatment did not alter the antitumor effect of 5-fluorouracil. In the CIM model, G-1 therapy reduced the expression of proapoptotic protein and cyclin D1 and cyclin B1, reversed the changes in the number of TUNEL+ cells, Ki67+ and bromodeoxyuridine+ cells in crypts. The selective GPER antagonist G15 eliminated all of the above effects caused by G-1 on CIM, and application of G15 alone increased the severity of CIM. GPER was predominantly expressed in ileal crypts, and G-1 inhibited the DNA damage induced by 5-fluorouracil in vivo and vitro, as confirmed by the decrease in the number of γH2AX+ cells in the crypts and the comet assay results. Referring to the data from GEO dataset we verified GPER activation restored ERK1/2 activity in CIM and 5-fluorouracil-treated IEC-6 cells. Once the effects of G-1 on ERK1/2 activity were abolished with the ERK1/2 inhibitor PD0325901, the effects of G-1 on DNA damage both in vivo and in vitro were eliminated. Correspondingly, all of the manifestations of G-1 protection against CIM were inhibited by PD0325901, such as body weight and histological changes, the mucosal barrier, the apoptosis and proliferation of crypt cells. In conclusion, GPER activation prevents CIM by inhibiting crypt cell DNA damage in an ERK1/2-dependent manner, suggesting GPER might be a target preventing CIM.

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Activation of G protein–coupled estrogen receptor protects intestine from ischemia/reperfusion injury in mice by protecting the crypt cell proliferation

Cited by 25 publications

References 70 publications

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

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

G Protein-Coupled Estrogen Receptor: A Potential Therapeutic Target in Cancer

Activation of G protein coupled estrogen receptor prevents chemotherapy-induced intestinal mucositis by inhibiting the DNA damage in crypt cell in an extracellular signal-regulated kinase 1- and 2- dependent manner

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