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Alpha-1 Antitrypsin Prevents the Development of Preeclampsia Through Suppression of Oxidative Stress
Yaling Feng1, Jianjuan Xu1, Qin Zhou2
1Department of Obstetrics and Gynecology, Wuxi Maternal and Child Health Hospital, Nanjing Medical University Wuxi, China.
Insights
Alpha-1 antitrypsin (AAT) levels are decreased in preeclampsia (PE). AAT therapy in mice reduced blood pressure and protein in urine, suggesting AAT as a potential treatment for PE.
Area of Science:
- Obstetrics and Gynecology
- Cardiovascular Research
- Cell Biology
Background:
- Preeclampsia (PE) is a leading cause of maternal and fetal mortality, characterized by unpredictable development and challenging clinical management.
- Oxidative stress is a key factor in PE pathogenesis.
- Previous research indicated Alpha-1 antitrypsin (AAT) protects vascular endothelial cells by reducing oxidative stress.
Purpose of the Study:
- To investigate the role of AAT in PE development.
- To identify the underlying mechanisms of AAT's effects in PE.
- To evaluate AAT as a potential therapeutic strategy for PE.
Main Methods:
- Quantification of AAT levels in placental tissues from PE patients and healthy controls.
- Administration of exogenous AAT to a mouse model of PE.
- Assessment of blood pressure and urine protein levels in treated mice.
- Measurement of oxidative stress markers (ROS, MMP9, MDA, SOD, eNOS, GPx) and signaling pathways (PAK/STAT1/p38) in response to AAT treatment.
- Validation of findings in human samples.
Main Results:
- AAT levels were significantly lower in placentas from women with PE compared to healthy controls.
- AAT injection dose-dependently reduced high blood pressure and urine protein levels in PE mice.
- AAT administration suppressed PE-induced oxidative stress by decreasing ROS, MMP9, and MDA, while increasing SOD, eNOS, and GPx.
- AAT treatment inactivated the PE-mediated activation of PAK/STAT1/p38 signaling pathways.
- These results were corroborated in human placental samples.
Conclusions:
- Exogenous AAT administration mitigates PE symptoms and pathological markers in a preclinical model.
- AAT functions by enhancing antioxidant capacity and suppressing oxidative stress.
- AAT exerts its protective effects through the inactivation of the STAT1/p38 signaling pathway.
- AAT represents a promising therapeutic candidate for preeclampsia treatment.
Abstract:
Preeclampsia (PE) and its complications have become the leading cause of maternal and fetal morbidity and mortality in the world. And the development of PE is still barely predictable and thus challenging to prevent and manage clinically. Oxidative stress contributes to the development of the disease. Our previous study demonstrated that exogenous Alpha-1 antitrypsin (AAT) played a cytoprotective role in vascular endothelial cell by suppressing oxidative stress. In this study, we aim to investigate whether AAT contributes to the development of PE, and to identify the mechanism behind these effects. We found that AAT levels were significantly decreased in placenta tissues from women with PE compared that of healthy women. Notably, we demonstrate that AAT injection is able to relieve the high blood pressure and reduce urine protein levels in a dose-dependent manner in PE mice. In addition, our results showed that AAT injection exhibited an anti-oxidative stress role by significantly reducing PE mediated-upregulation of ROS, MMP9 and MDA, and increasing the levels of SOD, eNOS, and GPx with increased dosage of AAT. Furthermore, we found that AAT injection inactivated PE mediated activation of PAK/STAT1/p38 signaling. These findings were confirmed in human samples. In conclusion, our study suggests that exogenous AAT injection increases the antioxidants and suppresses oxidative stress, and subsequent prevention of PE development through inactivation of STAT1/p38 signaling. Thus, AAT would become a potential strategy for PE therapy.
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