FGF21 alleviates pulmonary hypertension by inhibiting mTORC1/EIF4EBP1 pathway via H19

Li, Xiuchun; Zhang, Yaxin; Su, Lihuang; Cai, Luqiong; Zhang, Chi; Zhang, Jianhao; Sun, Junwei; Chai, Mengyu; Cai, Mengsi; Wu, Qian; Zhang, Chi; Yan, Xiaoqing; Wang, Liangxing; Huang, Xiaoying

doi:10.1111/jcmm.17318

Cited by 17 publications

(5 citation statements)

References 55 publications

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“…Different blood samples, different models, tissues and cell samples may have caused some discrepancies. 33 H19 with a primary structure up to 2.3 KB can act as a ceRNA to adsorb miRNA, thereby weakening its interference with the targeted mRNA. 29,34 Our ndings imply that H19 sponges let-7 g, which is consistent with a prior publication.…”

Section: Discussionmentioning

confidence: 99%

LncRNAH19 acts as a ceRNA of let-7g to facilitate EndMT in hypoxic pulmonary hypertension via regulating TGF-β signalling pathway

Yu,

Huang,

Liu

et al. 2024

Preprint

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Background Hypoxic pulmonary hypertension (HPH) is a challenging lung arterial disorder with remarkably high incidence and mortality rates, and the efficiency of current HPH treatment strategies is unsatisfactory. Endothelial-to-mesenchymal transition (EndMT) in the pulmonary artery plays a crucial role in HPH. Previous studies have shown that lncRNA-H19 (H19) is involved in many cardiovascular diseases by regulating cell proliferation and differentiation but the role of H19 in EndMT in HPH has not been defined. Methods In this research, the expression of H19 was investigated in PAH human patients and rat models. Then, we established a hypoxia-induced HPH rat model to evaluate H19 function in HPH by Echocardiography and hemodynamic measurements. Moreover, luciferase reporter gene detection, and western blotting were used to explore the mechanism of H19. Results Here, we first found that the expression of H19 was significantly increased in the endodermis of pulmonary arteries and that H19 deficiency obviously ameliorated pulmonary vascular remodelling and right heart failure in HPH rats, and these effects were associated with inhibition of EndMT. Moreover, an analysis of luciferase activity indicated that microRNA-let-7g (let-7g) was a direct target of H19. H19 deficiency or let-7g overexpression can markedly downregulate the expression of TGFβR1, a novel target gene of let-7g. Furthermore, inhibition of TGFβR1 induced similar effects to H19 deficiency. Conclusions In summary, our findings demonstrate that the H19/let-7g/TGFβR1 axis is crucial in the pathogenesis of HPH by stimulating EndMT. Our study may provide new ideas for further research on HPH therapy in the near future.

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Section: Discussionmentioning

confidence: 99%

LncRNAH19 acts as a ceRNA of let-7g to facilitate EndMT in hypoxic pulmonary hypertension via regulating TGF-β signalling pathway

Yu,

Huang,

Liu

et al. 2024

Preprint

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“…However, a recent study indicated that knockdown of H19 significantly promoted the proliferation of rPASMCs, which seems to contradict our finding. Different blood samples, different models, tissues and cell samples may have caused some discrepancies [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

LncRNAH19 acts as a ceRNA of let-7 g to facilitate endothelial-to-mesenchymal transition in hypoxic pulmonary hypertension via regulating TGF-β signalling pathway

Yu,

Huang,

Liu

et al. 2024

Respir Res

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Background Hypoxic pulmonary hypertension (HPH) is a challenging lung arterial disorder with remarkably high incidence and mortality rates, and the efficiency of current HPH treatment strategies is unsatisfactory. Endothelial-to-mesenchymal transition (EndMT) in the pulmonary artery plays a crucial role in HPH. Previous studies have shown that lncRNA-H19 (H19) is involved in many cardiovascular diseases by regulating cell proliferation and differentiation but the role of H19 in EndMT in HPH has not been defined. Methods In this research, the expression of H19 was investigated in PAH human patients and rat models. Then, we established a hypoxia-induced HPH rat model to evaluate H19 function in HPH by Echocardiography and hemodynamic measurements. Moreover, luciferase reporter gene detection, and western blotting were used to explore the mechanism of H19. Results Here, we first found that the expression of H19 was significantly increased in the endodermis of pulmonary arteries and that H19 deficiency obviously ameliorated pulmonary vascular remodelling and right heart failure in HPH rats, and these effects were associated with inhibition of EndMT. Moreover, an analysis of luciferase activity indicated that microRNA-let-7 g (let-7 g) was a direct target of H19. H19 deficiency or let-7 g overexpression can markedly downregulate the expression of TGFβR1, a novel target gene of let-7 g. Furthermore, inhibition of TGFβR1 induced similar effects to H19 deficiency. Conclusions In summary, our findings demonstrate that the H19/let-7 g/TGFβR1 axis is crucial in the pathogenesis of HPH by stimulating EndMT. Our study may provide new ideas for further research on HPH therapy in the near future.

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“…Damgaard RB's study revealed that OTULIN-de cient livers with steatohepatitis exhibit aberrant mTOR activation 18 . Additionally, FGF21 functions as an inhibitor of mTORC1 to regulate hepatic insulin action and maintain glucose homeostasis 19 . Li et al utilized complementary genetic models with gain or loss of function of mTOR signaling in the liver and demonstrated the bene cial effect of mTOR in liver IR injury 20 .…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells derived exosomes ameliorate D-galN/LPS induced acute liver injury via PTEN-mediated macrophage polarization

Zhang,

Fu,

Wei

et al. 2023

Preprint

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Background: It is widely acknowledged that Mesenchymal Stem Cells (MSCs) exert their effects through paracrine mechanisms by releasing bioactive components, such as exosomes, while previous studies have confirmed the critical role of macrophage polarization in acute liver injury, the impact of exosome-mediated liver repair on macrophage polarization requires further clarification. Methods: Human placental mesenchymal stem cell-derived exosomes (hPMSC-Exo) were intravenously administered to the mice 2 hours before exposure to LPS/GalN. The effects of hPMSC-Exo were evaluated using serum biochemical analysis, TUNEL assay, and H&E staining. In order to elucidate the mechanisms underlying acute liver injury therapy, the expression levels of relevant genes were evaluated using qPCR and WB analysis, respectively. The exosome transfected miR-26-5p were used for further determine the mTOR signaling in hPMSC-Exo based threapy. Results: hPMSC-Exo alleviated liver inflammation and promoted liver repair in a mouse model of D-galN/LPS-induced DILI (drug-induced liver injury). Subsequent investigations revealed that hPMSC-Exo induced the polarization of M1 macrophages towards an M2 phenotype, both in vivo and in vitro. Bioinformatics analysis identified miR-26-5p as a potential mediator of macrophage polarization and PTEN as its downstream target. Attenuation of macrophage polarization modulation was observed when miR-26-5p levels were reduced in hPMSC-Exo. Similarly, knockdown of PTEN also demonstrated hepatoprotective efficacy and reduced inflammation levels in a mouse model of DILI. Conclusion: Our findings suggest the involvement of the PTEN/mTOR/TGF-β1 signaling pathway in regulating macrophage activation through hPMSC exosomal miR-26-5p, highlighting its therapeutic potential in the treatment of liver injury.

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FGF21 alleviates pulmonary hypertension by inhibiting mTORC1/EIF4EBP1 pathway via H19

Cited by 17 publications

References 55 publications

LncRNAH19 acts as a ceRNA of let-7g to facilitate EndMT in hypoxic pulmonary hypertension via regulating TGF-β signalling pathway

LncRNAH19 acts as a ceRNA of let-7g to facilitate EndMT in hypoxic pulmonary hypertension via regulating TGF-β signalling pathway

LncRNAH19 acts as a ceRNA of let-7 g to facilitate endothelial-to-mesenchymal transition in hypoxic pulmonary hypertension via regulating TGF-β signalling pathway

Mesenchymal stem cells derived exosomes ameliorate D-galN/LPS induced acute liver injury via PTEN-mediated macrophage polarization

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