Redistribution of Extracellular Superoxide Dismutase Causes Neonatal Pulmonary Vascular Remodeling and PH but Protects Against Experimental Bronchopulmonary Dysplasia

Sherlock, Laurie; Trumpie, Ashley; Hernandez-Lagunas, Laura; McKenna, Sarah; Fisher, Susan J.; Bowler, Russell P.; Wright, Clyde J.; Delaney, Cassidy; Nozik, Eva S.

doi:10.3390/antiox7030042

Cited by 13 publications

(11 citation statements)

References 56 publications

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“…Secondly, we did not detect clear reductions in HA content or fragment size in wildtype mice during the course of chronic hypoxia. This implies that hypoxic HA fragmentation itself may not be a sufficient disease trigger, but that it may exacerbate or accelerate PH in susceptible backgrounds of altered extracellular redox status due to impaired SOD3 expression 10 , activity 66 , or localization 6,67 . Since our gel separation methods cannot resolve very low molecular weight and oligomeric HA species (≤50 kDa), we may have not captured the formation of these bioactive fragments in the lung tissue.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Superoxide Dismutase Regulates Early Vascular Hyaluronan Remodeling in Hypoxic Pulmonary Hypertension

Tseng

Allawzi

et al. 2020

Sci Rep

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chronic hypoxia leads to pathologic remodeling of the pulmonary vasculature and pulmonary hypertension (PH). The antioxidant enzyme extracellular superoxide dismutase (SOD3) protects against hypoxia-induced pH. Hyaluronan (HA), a ubiquitous glycosaminoglycan of the lung extracellular matrix, is rapidly recycled at sites of vessel injury and repair. We investigated the hypothesis that SOD3 preserves HA homeostasis by inhibiting oxidative and enzymatic hyaluronidase-mediated HA breakdown. In SOD3-deficient mice, hypoxia increased lung hyaluronidase expression and activity, hyaluronan fragmentation, and effacement of HA from the vessel wall of small pulmonary arteries. Hyaluronan fragmentation corresponded to hypoxic induction of the cell surface hyaluronidase-2 (Hyal2), which was localized in the vascular media. Human pulmonary artery smooth muscle cells (HPASMCs) demonstrated hypoxic induction of Hyal2 and SOD-suppressible hyaluronidase activity, congruent to our observations in vivo. fragmentation of homeostatic high molecular weight HA promoted HpASMc proliferation in vitro, whereas pharmacologic inhibition of hyaluronidase activity prevented hypoxia-and oxidant-induced proliferation. Hypoxia initiates SOD3-dependent alterations in the structure and regulation of hyaluronan in the pulmonary vascular extracellular matrix. these changes occurred soon after hypoxia exposure, prior to appearance of pH, and may contribute to the early pathogenesis of this disease.Pulmonary hypertension (PH) is an incurable and fatal disease characterized by intimal thickening, muscular hypertrophy, excessive matrix deposition, and stiffening of arteries in the lung. Chronic hypoxia is a major cause and consequence of PH in humans. It is the most prevalent etiology of precapillary PH in humans (WHO Group 3 disease). The onset of PH in patients with hypoxia due to intrinsic lung disease portends a grim prognosis for survival, post-transplant outcome, and quality of life 1,2 . Therefore, there is an urgent need for research on the molecular pathogenesis of hypoxic pulmonary hypertension.One facet of this disease is the presence of high oxidative stress within the vessel wall and perivascular matrix 3 . Extracellular superoxide dismutase (SOD3) is crucial for neutralization of this stress. Global knockout 4 , selective deletion from smooth muscle cells 5 , and disrupted matrix-binding single nucleotide polymorphisms 6 of SOD3 result in a great susceptibility to hypoxia-induced vascular inflammation, fibrosis, and PH. On the other hand, lung-specific overexpression of SOD3 7 , adenoviral gene transfer of human SOD3 8 , and treatment with an inorganic metalloporphyrin SOD3 mimetic 9 are protective against PH in rodent models. In the advanced stages of PH in humans, SOD3 levels are epigenetically reduced by histone deacetylation 10 .There is a critical gap in our understanding of how the extracellular oxidative environment can lead to irreversible pulmonary vascular remodeling in chronic hypoxia. Amassing evidence points to a central role f...

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Section: Discussionmentioning

confidence: 99%

Extracellular Superoxide Dismutase Regulates Early Vascular Hyaluronan Remodeling in Hypoxic Pulmonary Hypertension

Tseng

Allawzi

et al. 2020

Sci Rep

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“…Alteration in ECSOD expression is associated with disease in these tissues, and polymorphisms of ECSOD have been identified to contribute to lung and cardiovascular disease. In the primary article by Sherlock et al [ 14 ], the authors show that a polymorphism of ECSOD, R213G, results in more ECSOD in the serum and less ECSOD bound to the vasculature. The R213G ECSOD mice have abnormal pulmonary vascular development but are better protected from lung injury.…”

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confidence: 99%

Superoxide Dismutases (SODs) and SOD Mimetics

Borgstahl

Oberley‐Deegan

2018

Antioxidants

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“…Chen et al recently found that SOD activity in BPD mice was decreased with the enhancement of MDA level [ 20 ], which is consistent with our findings. In a related research, it was discovered that increased SOD activity could treat lung damage and hypertension in BPD patients [ 21 ]. It was reported that enhancement of MDA level triggered hyperoxia-induced oxidative stress, which aggravated lung damage and impeded vascular and pulmonary tissue growth [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Silencing of Long Non-Coding RNA X Inactive Specific Transcript (Xist) Contributes to Suppression of Bronchopulmonary Dysplasia Induced by Hyperoxia in Newborn Mice via microRNA-101-3p and the transforming growth factor-beta 1 (TGF-β1)/Smad3 Axis

et al. 2020

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Background Bronchopulmonary dysplasia (BPD) is a chronic lung disease mostly affecting premature infants. Long non-coding RNA (lncRNA) X inactive specific transcript (Xist) is actively involved in pulmonary disease development. The present study explored the potential mechanism of Xist in BPD development. Material Methods First, newborn BPD mouse models were successfully established. lncRNAs and genes with differential expression were identified using microarray analysis. Various injuries and radial alveolar counts of lung tissues of BPD mice were detected by hematoxylin-eosin staining. Functional assays were utilized to detect alterations of superoxide dismutase (SOD), malondialdehyde (MDA), vascular endothelial growth factor, collagen I, alpha-smooth muscle Actin, TGF-β1, and Smad3. Then, dual-luciferase reporter gene assay and RNA pull-down assay were performed to clarify the targeting relationship between Xist and miR-101-3p and between miR-101-3p and high-mobility group protein B3 (HMGB3). Results In BPD mice, radial alveolar counts value and SOD activity declined while MDA level increased. Results of microarray analysis found that Xist and HMGB3 were highly expressed in BPD mice. Next, silenced Xist alleviated lung damage in BPD mice. Xist competitively bound to miR-101-3p to activate HMGB3, and overexpressed miR-101-3p mitigated lung damage in BPD mice. Additionally, silenced Xist downregulated the TGF-β1/Smad3 axis. Conclusions Our study demonstrated that silencing of Xist suppressed BPD development by binding to miR-101-3p and downregulating HMGB3 and the TGF-β1/Smad3 axis. Our results may provide novel insights for BPD treatment.

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Redistribution of Extracellular Superoxide Dismutase Causes Neonatal Pulmonary Vascular Remodeling and PH but Protects Against Experimental Bronchopulmonary Dysplasia

Cited by 13 publications

References 56 publications

Extracellular Superoxide Dismutase Regulates Early Vascular Hyaluronan Remodeling in Hypoxic Pulmonary Hypertension

Extracellular Superoxide Dismutase Regulates Early Vascular Hyaluronan Remodeling in Hypoxic Pulmonary Hypertension

Superoxide Dismutases (SODs) and SOD Mimetics

Silencing of Long Non-Coding RNA X Inactive Specific Transcript (Xist) Contributes to Suppression of Bronchopulmonary Dysplasia Induced by Hyperoxia in Newborn Mice via microRNA-101-3p and the transforming growth factor-beta 1 (TGF-β1)/Smad3 Axis

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