Mitochondrial Fission-Mediated Lung Development in Newborn Rats With Hyperoxia-Induced Bronchopulmonary Dysplasia With Pulmonary Hypertension

Dai, Yongqiang; Yu, Binyuan; Ai, Danyang; Lin, Yuan; Huo, Ran; Fu, Xiaoqin; Chen, Shangqin; Chen, Chao

doi:10.3389/fped.2020.619853

Cited by 9 publications

(6 citation statements)

References 37 publications

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“…In the previous study about the hyperoxia-induced bronchopulmonary dysplasia animal model, the expression and phosphorylation of Drp1 increased in lung tissues. When Drp1 expression was inhibited, the small pulmonary vessel development improved, and pulmonary hypertension was relieved ( 49 ). DRP1 also plays a vital role in heart development, and DRP1 knockout mice exhibited fatal cardiac defects ( 50 ).…”

Section: Discussionmentioning

confidence: 99%

Effects of Excessive Activation of N-methyl-D-aspartic Acid Receptors in Neonatal Cardiac Mitochondrial Dysfunction Induced by Intrauterine Hypoxia

Liu

Luo

Liao

et al. 2022

Front. Cardiovasc. Med.

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Intrauterine hypoxia is a common complication during pregnancy and could increase the risk of cardiovascular disease in offspring. However, the underlying mechanism is controversial. Memantine, an NMDA receptor antagonist, is reported to be a potential cardio-protective agent. We hypothesized that antenatal memantine treatment could prevent heart injury in neonatal offspring exposed to intrauterine hypoxia. Pregnant rats were exposed to gestational hypoxia or antenatal memantine treatment during late pregnancy. Newborns were then sacrificed to assess multiple parameters. The results revealed that Intrauterine hypoxia resulted in declining birth weight, heart weight, and an abnormally high heart weight/birth weight ratio. Furthermore, intrauterine hypoxia caused mitochondrial structural, functional abnormalities and decreased expression of DRP1, and upregulation of NMDAR1 in vivo. Antenatal memantine treatment,an NMDARs antagonist, improved these changes. In vitro, hypoxia increased the glutamate concentration and expression of NMDAR1. NMDAR activation may lead to similar changes in mitochondrial function, structure, and downregulation of DRP1 in vitro. Pharmacological blockade of NMDARs by the non-competitive NMDA antagonist MK-801 or knockdown of the glutamate receptor NR1 significantly attenuated the increased mitochondrial reactive oxygen species and calcium overload-induced by hypoxia exposure. These facts suggest that memantine could provide a novel and promising treatment for clinical use in intrauterine hypoxia during pregnancy to protect the cardiac mitochondrial function in the offspring. To our best knowledge, our research is the first study that shows intrauterine hypoxia can excessively activate cardiac NMDARs and thus cause mitochondrial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Effects of Excessive Activation of N-methyl-D-aspartic Acid Receptors in Neonatal Cardiac Mitochondrial Dysfunction Induced by Intrauterine Hypoxia

Liu

Luo

Liao

et al. 2022

Front. Cardiovasc. Med.

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“…Excessive fission has been shown to contribute to cardiac injury under certain conditions such as pressure-overload, ischemia, and doxorubicin treatment [50,51]. A previous study also confirmed that excessive mitochondrial fission is an important mediator of hyperoxia-induced pulmonary vascular injury [52]. Intermittent hypobaric hypoxia-induced preconditioning in rats was reported to assist the lung to adapt to severe hypoxic conditions by stabilizing mitochondrial function [53].…”

Section: Discussionmentioning

confidence: 82%

Downregulation of SIRT3 Aggravates Lung Ischemia Reperfusion Injury by Increasing Mitochondrial Fission and Oxidative Stress through HIF-1α-Dependent Mechanisms

Liu

Pei

Dai

et al. 2022

Oxidative Medicine and Cellular Longevity

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Lung ischemia-reperfusion injury (LIRI) is a severe multifaceted pathological condition that can lead to poor patient outcome where oxidative stress and the resulting inflammatory response can trigger and exacerbate tissue damage in LIRI patients. Sirtuin3 (SIRT3), a member of the sirtuin family, protects against oxidative stress-related diseases. However, it remains unclear if and how SIRT3 alleviates lung injury induced by ischemia/reperfusion (I/R). Our previous study showed that lung tissue structures were severely damaged at 6 h after lung I/R in mice, however, repair of the injured lung tissue was significant at 24 h. In this study, we found that both SIRT3 mRNA and protein levels were markedly increased at 24 h after lung I/R in vivo. Meanwhile, inhibition of SIRT3 aggravated lung injury and inflammation, augmented mitochondrial fission and oxidative stress and increased Hypoxia-inducible factor-1α (HIF-1α) expression in vivo. The results suggest that SIRT3 may be an upstream regulator of HIF-1α expression. Knockdown of SIRT3 resulted in excessive mitochondrial fission and increased oxidative stress in vitro, and we found that knocking down the expression of HIF-1α alleviated these changes. This suggests that the SIRT3-HIF-1α signaling pathway is involved in regulating mitochondrial function and oxidative stress. Furthermore, inhibition of dynamin-related protein 1 (Drp-1) by the inhibitor of mitophagy, Mdivi-1, blocked mitochondrial fission and alleviated oxidative stress in vitro. Taken together, our results demonstrated that downregulation of SIRT3 aggravates LIRI by increasing mitochondrial fission and oxidative stress. Activation of SIRT3 inhibits mitochondrial fission and this mechanism may serve as a new therapeutic strategy to treat LIRI.

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“…In the PAH models induced by medicines or hypoxia, researchers found an increase in mitochondrial fragments and a decrease in functioning mitochondria stimulated by Drp1 overexpression, which showed as the inhibition of aerobic glucose metabolism and aberrant glycolysis ( Boehme et al, 2016 ; Parra et al, 2017 ; Tian et al, 2018 ; Dai et al, 2021 ). These results could confirm that Drp1 upregulation in PAH enhances mitochondrial fission.…”

Section: Dynamin-related Protein 1-mediated Mitochondrial Homeostasis...mentioning

confidence: 99%

“…The mitochondrial metabolism function was then restored, and PASMC hyperproliferation was inhibited. In addition, the hyperoxia-induced neonatal rat model displayed bronchopulmonary dysplasia, which was followed by PAH ( Dai et al, 2021 ). Meanwhile, they found an increase in Drp1 expression at the beginning of alveolar development in neonatal rats.…”

Section: Role Of Dynamin-related Protein 1 For Mitochondrial Fission ...mentioning

confidence: 99%

Inhibitors of Mitochondrial Dynamics Mediated by Dynamin-Related Protein 1 in Pulmonary Arterial Hypertension

Xiao

Zhang

Wang

2022

Front. Cell Dev. Biol.

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Pulmonary arterial hypertension (PAH) is a chronic, lethal pulmonary disease characterized by pulmonary vascular remodeling. It leads to malignant results, such as rupture of pulmonary arterial dissection, dyspnea, right heart failure, and even death. Previous studies have confirmed that one of the main pathological changes of this disease is abnormal mitochondrial dynamics, which include mitochondrial fission, fusion, and autophagy that keep a dynamic balance under certain physiological state. Dynamin-related protein 1 (Drp1), the key molecule in mitochondrial fission, mediates mitochondrial fission while also affecting mitochondrial fusion and autophagy through numerous pathways. There are various abnormalities of Drp1 in PAH pathophysiology, including Drp1 overexpression and activation as well as an upregulation of its outer mitochondrial membrane ligands. These aberrant alterations will eventually induce the development of PAH. With the process of recent studies, the structure and function of Drp1 have been gradually revealed. Meanwhile, inhibitors targeting this pathway have also been discovered. This review aims to shed more light on the mechanism of Drp1 and its inhibitors in the abnormal mitochondrial dynamics of PAH. Furthermore, it seeks to provide more novel insights to clinical therapy.

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Mitochondrial Fission-Mediated Lung Development in Newborn Rats With Hyperoxia-Induced Bronchopulmonary Dysplasia With Pulmonary Hypertension

Cited by 9 publications

References 37 publications

Effects of Excessive Activation of N-methyl-D-aspartic Acid Receptors in Neonatal Cardiac Mitochondrial Dysfunction Induced by Intrauterine Hypoxia

Effects of Excessive Activation of N-methyl-D-aspartic Acid Receptors in Neonatal Cardiac Mitochondrial Dysfunction Induced by Intrauterine Hypoxia

Downregulation of SIRT3 Aggravates Lung Ischemia Reperfusion Injury by Increasing Mitochondrial Fission and Oxidative Stress through HIF-1α-Dependent Mechanisms

Inhibitors of Mitochondrial Dynamics Mediated by Dynamin-Related Protein 1 in Pulmonary Arterial Hypertension

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