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Isolation of Pulmonary Artery Smooth Muscle Cells from Neonatal Mice
Published on: October 19, 2013
Inhibition of mitochondrial integrated stress response ameliorates ibuprofen-induced endothelial dysfunction in
Xuan Wang1, Bingchun Lin1, Lingling Yang1
1Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, Women and Children's Medical Center, Shenzhen School of Clinical Medicine, Southern Medical University, Shenzhen, Guangdong Province, China.
Insights
Ibuprofen impairs blood vessel formation in premature infants by affecting mitochondria. An ISR inhibitor (ISRIB) protected against this damage, offering a potential treatment for bronchopulmonary dysplasia (BPD).
Area of Science:
- Biomedical research
- Molecular biology
- Neonatal medicine
Background:
- Ibuprofen treats patent ductus arteriosus (PDA) in premature infants but can harm blood vessel formation (angiogenesis), potentially causing bronchopulmonary dysplasia (BPD).
- The exact molecular reasons for ibuprofen's anti-angiogenic effects, especially when combined with oxygen therapy, are not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms behind ibuprofen's anti-angiogenic effects in endothelial cells.
- To evaluate the potential of an integrated stress response (ISR) inhibitor (ISRIB) to counteract ibuprofen-induced endothelial dysfunction.
Main Methods:
- Examined the impact of ibuprofen on mitochondrial function in human endothelial cells.
- Investigated the combined effects of ibuprofen and hyperoxia on the mitochondrial integrated stress response (ISR).
- Assessed the protective effects of ISRIB on endothelial cells and in a mouse model of BPD.
Main Results:
- Ibuprofen alone impaired mitochondrial function; combined with hyperoxia, it triggered a heightened ISR, leading to endothelial dysfunction.
- Pretreatment with ISRIB improved mitochondrial function and angiogenic capacity in cells exposed to ibuprofen and hyperoxia.
- In vivo, prophylactic ISRIB treatment reduced ISR signaling and partially improved lung angiogenesis in ibuprofen-treated BPD mice.
Conclusions:
- Pathological ISR driven by ibuprofen and hyperoxia contributes to endothelial dysfunction in BPD.
- ISRIB shows promise as a prophylactic treatment to protect against ibuprofen-induced endothelial damage in premature infants with PDA.
Abstract:
Ibuprofen is a nonsteroidal anti-inflammatory drug with promising activity against patent ductus arteriosus (PDA) in premature infants, but its adverse effect on angiogenesis has hampered the clinical benefit and contributed to development of bronchopulmonary dysplasia (BPD). However, the molecular mechanisms underlying its anti-angiogenic effect have remained incompletely understood. Here we show that ibuprofen compromised mitochondrial function in human endothelial cells, and when used in combination with oxygen therapy-the life-saving respiratory support that preterm infants rely on, ibuprofen and hyperoxia cooperated to activate a heightened mitochondrial integrated stress response (ISR) which resulted in mitochondrial dysfunction and subsequent endothelial defect. In contrast, human endothelial cells pretreated with ISR inhibitor (ISRIB) show significantly enhanced mitochondrial bioenergetics and improved endothelial angiogenic capacity following combination treatment of ibuprofen and hyperoxia. Furthermore, prophylactic ISRIB treatment in vivo reduced ISR signaling in lung endothelial cells and partially improved angiogenesis in ibuprofen-treated BPD mouse lungs. Our findings demonstrate the prophylactic effectiveness of ISRIB against pathologic ISR in driving endothelial dysfunction, thus offering an attractive preventive approach for PDA patients undergoing treatment with ibuprofen and hyperoxia.
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