Hypoxia-induced microRNA-191 contributes to hepatic ischemia/reperfusion injury through the ZONAB/Cyclin D1 axis

Pan, Wen-Ming; Wang, Lin; Zhang, Xiaofei; Zhang, Hongji; Zhang, Jinxiang; Wang, Guoliang; Xu, Peng; Zhang, Yunwei; Hu, Ping; Zhang, Xiaodong; Du, Ran; Wang, Hui

doi:10.1038/s41418-018-0120-9

Cited by 44 publications

(35 citation statements)

References 41 publications

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“…Knockdown of miR-191 could reduce the infarction area induced by MCAO in rats and promote proliferation, migration, tube formation and spheroid sprouting in HUVEC. Our results complement nicely with a previous report showing that knockout of miR-191 reduced hepatic ischemia-reperfusion injury through inhibiting inflammatory responses and cell death [41]. Another study also showed that up-regulated miR-191 participated in renal ischemia-reperfusion injury via inducing apoptosis of renal tubular epithelial cells [42].…”

Section: Discussionsupporting

confidence: 91%

MiR-191 inhibit angiogenesis after acute ischemic stroke targeting VEZF1

Zhao

Wang

et al. 2019

Aging

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Acute ischemic stroke (AIS) is a major public health problem in China. Impaired angiogenesis plays crucial roles in the development of ischemic cerebral injury. Recent studies have identified that microRNAs (miRNAs) are important regulators of angiogenesis, but little is known the exact effects of angiogenesis-associated miRNAs in AIS. In the present study, we detected the expression levels of angiogenesis-associated miRNAs in AIS patients, middle cerebral artery occlusion (MCAO) rats, and oxygen-glucose deprivation/reoxygenation (OGD/R) human umbilical vein endothelial cells (HUVECs). MiR-191 was increased in the plasma of AIS patients, OGD/R HUVECs, and the plasma and brain of MCAO rats. Over-expression of miR-191 promoted apoptosis, but reduced the proliferation, migration, tube-forming and spheroid sprouting activity in HUVECs OGD/R model. Mechanically, vascular endothelial zinc finger 1 (VEZF1) was identified as the direct target of miR-191, and could be regulated by miR-191 at post-translational level. In vivo studies applying miR-191 antagomir demonstrated that inhibition of miR-191 reduced infarction volume in MCAO rats. In conclusion, our data reveal a novel role of miR-191 in promoting ischemic brain injury through inhibiting angiogenesis via targeting VEZF1. Therefore, miR-191 may serve as a biomarker or a therapeutic target for AIS.

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Section: Discussionsupporting

confidence: 91%

MiR-191 inhibit angiogenesis after acute ischemic stroke targeting VEZF1

Zhao

Wang

et al. 2019

Aging

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“…Hepatic ischemia-reperfusion (IR) injury induces high morbidity and mortality of patients following liver resection and transplantations 1 , 2 As reported, it is the leading cause of liver dysfunction and failure after liver surgery or transplantation, and satisfactory strategies to ameliorate hepatic IR injury are limited. 3 Emerging studies have unraveled the involvement of significant cell death and inflammatory responses 4 and oxidative stress and tissue damage 5 in hepatic IR injury. Interestingly, NLRP3 inflammasome activation has been reported to possess a critical function in hepatic IR injury.…”

Section: Introductionmentioning

confidence: 99%

SIRT1 alleviates hepatic ischemia-reperfusion injury via the miR-182-mediated XBP1/NLRP3 pathway

Zhang

Xue

et al. 2021

Molecular Therapy - Nucleic Acids

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The hepatoprotection of histone deacetylase sirtuin 1 (SIRT1) has been identified to attenuate ischemia-reperfusion (IR)-triggered inflammation and liver damage. This study was performed to characterize the function of SIRT1 in hepatic IR injury. In in vivo assays on liver-specific knockout mice of SIRT1, we first validated the effect of SIRT1 knockout on liver damage and XBP1/NLRP3 inflammasome activation. Next, we examined whether knockdown of XBP1/NLRP3 or miR-182 agomir could reverse the effect of SIRT1 knockout. In in vitro assays, NCTC1469 cells subjected to hypoxia/reoxygenation (H/R) were transduced with small interfering RNA (siRNA)/activator of SIRT1 or miR-182 agomir to confirm the effect of SIRT1 on NCTC1469 cell behaviors as well as the regulation of miR-182 and the XBP1/NLRP3 signaling pathway. Hepatic IR injury was appreciably aggravated in SIRT1 knockout mice, and SIRT1 knockdown abolished the inhibition of XBP1/NLRP3 inflammasome activation, which was reversed by NLRP3 knockdown, XBP1 knockdown, or miR-182 agomir. Mechanistically, miR-182 expression was positively regulated by SIRT1 in hepatic IR injury in mice, and miR-182 inhibited the expression of XBP1 by binding to the 3′ untranslated region (UTR) of XBP1. The histone deacetylase SIRT1 inhibits the downstream XBP1/NLRP3 inflammatory pathway by activating miR-182, thus alleviating hepatic IR injury in mice.

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“…Nonlethal segmental (70%) liver ischemia was performed as previously described. ( 20 ) Mice were sacrificed after 1 hour of ischemia and 6 hours of reperfusion. The isolation of hepatocytes from IR‐model mice livers was briefly summarized as the livers were excised, minced, and strained through a steel mesh, then purified by low‐speed centrifugation (3 times at 50 g for 5 minutes each).…”

Section: Methodsmentioning

confidence: 99%

miR‐210 Participates in Hepatic Ischemia Reperfusion Injury by Forming a Negative Feedback Loop With SMAD4

et al. 2020

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Background and Aims Hepatic ischemia‐reperfusion (IR) injury is a major complication of liver transplantation, resection, and hemorrhagic shock. Hypoxia is a key pathological event associated with IR injury. MicroRNA‐210 (miR‐210) has been characterized as a micromanager of hypoxia pathway. However, its function and mechanism in hepatic IR injury is unknown. Approach and Results In this study, we found miR‐210 was induced in liver tissues from patients subjected to IR‐related surgeries. In a murine model of hepatic IR, the level of miR‐210 was increased in hepatocytes but not in nonparenchymal cells. miR‐210 deficiency remarkably alleviated liver injury, cell inflammatory responses, and cell death in a mouse hepatic IR model. In vitro, inhibition of miR‐210 decreased hypoxia/reoxygenation (HR)–induced cell apoptosis of primary hepatocytes and LO2 cells, whereas overexpression of miR‐210 increased cells apoptosis during HR. Mechanistically, miR‐210 directly suppressed mothers against decapentaplegic homolog 4 (SMAD4) expression under normoxia and hypoxia condition by directly binding to the 3′ UTR of SMAD4. The pro‐apoptotic effect of miR‐210 was alleviated by SMAD4, whereas short hairpin SMAD4 abrogated the anti‐apoptotic role of miR‐210 inhibition in primary hepatocytes. Further studies demonstrated that hypoxia‐induced SMAD4 transported into nucleus, in which SMAD4 directly bound to the promoter of miR‐210 and transcriptionally induced miR‐210, thus forming a negative feedback loop with miR‐210. Conclusions Our study implicates a crucial role of miR‐210‐SMAD4 interaction in hepatic IR‐induced cell death and provides a promising therapeutic approach for liver IR injury.

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Hypoxia-induced microRNA-191 contributes to hepatic ischemia/reperfusion injury through the ZONAB/Cyclin D1 axis

Cited by 44 publications

References 41 publications

MiR-191 inhibit angiogenesis after acute ischemic stroke targeting VEZF1

MiR-191 inhibit angiogenesis after acute ischemic stroke targeting VEZF1

SIRT1 alleviates hepatic ischemia-reperfusion injury via the miR-182-mediated XBP1/NLRP3 pathway

miR‐210 Participates in Hepatic Ischemia Reperfusion Injury by Forming a Negative Feedback Loop With SMAD4

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