<scp>OBG</scp>‐like <scp>ATP</scp>ase 1 inhibition attenuates angiotensin <scp>II</scp>‐induced hypertrophic response in human ventricular myocytes via <scp>GSK</scp>‐3beta/beta‐catenin signalling

Narasimhan, Gayathri; Henderson, John; Luong, Hien; Rajasekaran, Namakkal Soorapan; Qin, Gangjian; Zhang, Jianyi; Krishnamurthy, Prasanna

doi:10.1111/1440-1681.13101

Cited by 11 publications

(24 citation statements)

References 25 publications

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“…5 B). Our previous study showed that OLA1 directly interacted with GSK3β and inhibited its activity [ 21 , 22 ], which is also proved by other study [ 23 , 24 ]. Meanwhile, GSK3β can phosphorylate HIF1α and facilitate its degradation [ 25 ], which can explain why HIF1α decreased in OLA1-KO CRC cell lines.…”

Section: Resultssupporting

confidence: 68%

OLA1 promotes colorectal cancer tumorigenesis by activation of HIF1α/CA9 axis

Liu

Kong

et al. 2022

BMC Cancer

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Background Obg-like ATPase 1 (OLA1) is a highly conserved GTPase, which was over expressed in a variety of malignant tumors, but its role in colorectal cancer (CRC) was poorly studied. Patients and methods Three public CRC gene databases were applied for OLA1 mRNA expression detection. The clinical data of 111 CRC patients were retrospectively collected from the Second Affiliated Hospital of Zhejiang University (SAHZU) for OLA1 protein expression and Kaplan-Meier Survival analysis. OLA1 stably knocked out CRC cell lines were conducted by CRISPR-Cas9 for experiments in vitro and in vivo. Results OLA1 was highly expressed in 84% CRC compared to matched surrounding tissues. Patients with OLA1 high expression had a significantly lower 5-year survival rate (47%) than those with OLA1 low expression (75%). OLA1 high expression was an independent factor of poor prognosis in CRC patients. OLA1-KO CRC cell lines showed lower ability of growth and tumorigenesis in vitro and in vivo. By mRNA sequence analysis, we found 113 differential express genes in OLA1-KO cell lines, of which 63 were hypoxic related. HIF1α was a key molecule in hypoxic regulation. Further molecular mechanisms showed HIF1α /CA9 mRNA and/or protein levels were heavily downregulated in OLA1-KO cell lines, which could explain the impaired tumorigenesis. According to previous studies, HIF1α was a downstream gene of GSK3β, we verified GSK3β was over-activated in OLA1-KO cell lines. Conclusion OLA1 was a new gene that was associated with carcinogenesis and poor outcomes in CRC by activation of HIF1α/CA9 axis, which may be interpreted by GSK3β.

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Section: Resultssupporting

confidence: 68%

OLA1 promotes colorectal cancer tumorigenesis by activation of HIF1α/CA9 axis

Liu

Kong

et al. 2022

BMC Cancer

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“…GSK-3 β has been shown to play vital roles in various biological processes and has shown to be a downstream mediator for Ang II. Narasimhan et al reported that inhibiting OBG-like ATPase alleviated the Ang II/GSK-3 β -induced hypertrophic response [ 30 , 52 ]. In addition, Ang II-mediated GSK-3 β signaling promoted muscle waste [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, GSK-3 β /mTOR signaling has been shown to regulate autophagy [ 28 ], but inhibition of GSK-3 β /mTOR could induce synaptogenesis and axonal repair in a neonatal rat model of HIE [ 29 ]. It was suggested that GSK-3 β was a downstream target for Ang II [ 30 ]. However, it remains unclear whether Ang II regulates GSK-3 β /mTOR activity.…”

Section: Introductionmentioning

confidence: 99%

AT1R/GSK-3β/mTOR Signaling Pathway Involved in Angiotensin II-Induced Neuronal Apoptosis after HIE Both In Vitro and In Vivo

Wei

Lenahan³

et al. 2020

Oxidative Medicine and Cellular Longevity

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Objective. The focus of the present study is to evaluate the effects of Angiotensin II (Ang II) on neuronal apoptosis after HIE and the potential underlying mechanisms. Methods. Primary neonatal rat cortical neurons were used to study the oxygen-glucose deprivation (OGD) cell model. The expressions of Ang II, AT1R, GSK-3β, p-GSK-3β, mTOR, p-mTOR, Bax, Bcl-2, and cleaved caspase-3 were detected via western blot. IF and flow cytometry were used to evaluate neuronal apoptosis. Hypoxic-ischemic encephalopathy (HIE) was established to evaluate the therapeutic effects of Ang II in vivo. Cerebral infarction areas were detected by 2,3,5-Triphenyltetrazolium chloride staining. The righting and geotaxis reflexes were also recorded. In addition, Fluoro-Jade C staining and TUNEL staining were performed to evaluate neuronal degeneration and apoptosis. Results. Ang II significantly increased the rate of neuronal apoptosis, upregulated the expression of cleaved caspase-3, and downregulated Bcl-2/Bax ratio after OGD insult. For vivo assay, the expressions of endogenous Ang II and AT1R gradually increased and peaked at 24 h after HIE. Ang II increased NeuN-positive AT1R cell expression. In addition, Ang II increased the area of cerebral infarction, promoted neuronal degeneration and apoptosis, aggravated neurological deficits on righting and geotaxis reflexes, and was accompanied by increased expressions of phosphorylated GSK-3β and mTOR. The application of valsartan (Ang II inhibitor) or SB216763 (GSK-3β inhibitor) reversed these phenomena triggered by Ang II following HIE. Conclusion. Ang II increased neuronal apoptosis through the AT1R/GSK-3β/mTOR signaling pathway after experimental HIE both in vitro and in vivo, and Ang II may serve as a novel therapeutic target to ameliorate brain injury after HIE.

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“…Glycogen synthase kinase-3β (GSK3β) is a serine-threonine kinase, which involves in some cellular signaling pathways 22. GSK3β signaling has been implicated in cardiac disease and human cancers 23. However, little is known about the role of GSK3β in spermiogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, it has been reported that male hypogonadism was associated with microRNAs (miRNAs) 24. Evidences indicated that microRNA-26a (miR-26a) plays important roles in tumor cells and neural stem cells; however, the function of miR-26a during male hypogonadism remains unclear 23,25. Although previous studies have reported that Rg3 had multiple pharmacological functions, the mechanisms by which Rg3 regulates the proliferation and apoptosis in MLTC-1 cells against TP remain unclear.…”

Section: Introductionmentioning

confidence: 99%

<p>Ginsenoside Rg3 protects mouse leydig cells against triptolide by downregulation of miR-26a</p>

Liang

Zhang

2019

DDDT

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Background Ginsenoside Rg3 has been reported to exert protection function on germ cells. However, the mechanisms by which Rg3 regulates apoptosis in mouse Leydig cells remain unclear. In addition, triptolide (TP) has been reported to induce infertility in male rats. Thus, this study aimed to investigate the protective effect of Rg3 against TP-induced toxicity in MLTC-1 cells. Methods CCK-8, immunofluorescence assay, Western blotting and flow cytometry were used to detect cell proliferation and cell apoptosis, respectively. In addition, the dual luciferase reporter system assay was used to detect the interaction between miR-26a and GSK3β in MLTC-1 cells. Results TP significantly inhibited the proliferation of MLTC-1 cells, while the inhibitory effect of TP was reversed by Rg3. In addition, TP markedly induced apoptosis in MLTC-1 cells via increasing the expressions of Bax, active caspase 3, Cyto c and active caspase 9, and decreasing the level of Bcl-2. However, Rg3 alleviated TP-induced apoptosis of MLTC-1 cells. Moreover, the level of miR-26a was obviously downregulated by Rg3 treatment. The protective effect of Rg3 against TP-induced toxicity in MLTC-1 cells was abolished by miR-26a upregulation. Meanwhile, dual-luciferase assay showed GSK3β was the direct target of miR-26a in MLTC-1 cells. Overexpression of miR-26a markedly decreased the level of GSK3β. As expected, upregulation of miR-26a could abrogate the protective effects of Rg3 against TP-induced cytotoxicity via inhibiting the expression of GSK3β. Conclusion These results indicated that Rg3 could protect MLTC-1 against TP by downregulation of miR-26a. Therefore, Rg3 might serve as a potential agent for the treatment of male hypogonadism.

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OBG‐like ATPase 1 inhibition attenuates angiotensin II‐induced hypertrophic response in human ventricular myocytes via GSK‐3beta/beta‐catenin signalling

Cited by 11 publications

References 25 publications

OLA1 promotes colorectal cancer tumorigenesis by activation of HIF1α/CA9 axis

OLA1 promotes colorectal cancer tumorigenesis by activation of HIF1α/CA9 axis

AT1R/GSK-3β/mTOR Signaling Pathway Involved in Angiotensin II-Induced Neuronal Apoptosis after HIE Both In Vitro and In Vivo

<p>Ginsenoside Rg3 protects mouse leydig cells against triptolide by downregulation of miR-26a</p>

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