Regulation of p38 mitogen-activated kinase-mediated fetal membrane senescence by statins
Martina T Ayad1, Brandie D Taylor2, Ramkumar Menon1
1Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine & Perinatal Research, The University of Texas Medical Branch at Galveston, Galveston, TX, USA.
Insights
Statins like simvastatin and rosuvastatin can prevent oxidative stress-induced preterm birth by downregulating p38MAPK-mediated senescence and inflammation in fetal membranes. Progesterone was ineffective in these models.
Area of Science:
- Reproductive biology
- Molecular mechanisms of parturition
- Oxidative stress and inflammation
Background:
- Oxidative stress (OS) contributes to chorioamniotic senescence and inflammation, linked to preterm birth (PTB) and preterm premature rupture of membranes (pPROM).
- p38 mitogen-activated protein kinase (p38MAPK) signaling mediates senescence and the senescence-associated secretory phenotype (SASP) in response to OS.
- Premature senescence in fetal membranes is a key factor in PTB and pPROM.
Purpose of the Study:
- To investigate the potential of simvastatin, rosuvastatin, and progesterone to inhibit OS-induced p38MAPK activation, senescence, and SASP in human fetal membranes.
- To determine the efficacy of statins and progesterone in preventing the molecular changes associated with preterm birth.
Main Methods:
- Human term fetal membranes were exposed to cigarette smoke extract (CSE) as an OS inducer.
- Treatments included simvastatin, rosuvastatin, and progesterone at specified concentrations.
- p38MAPK activation was assessed by Western blot, senescence by SA-β-Gal staining, and SASP markers (IL-8, IL-10, TNF-α, GM-CSF) by multiplex analysis.
Main Results:
- CSE significantly induced p38MAPK activation, senescence, and SASP markers.
- Simvastatin and rosuvastatin dose-dependently reduced p38MAPK activation, senescence, and key SASP markers (GM-CSF, TNF-α), while increasing IL-10.
- Progesterone treatment did not significantly alter CSE-induced p38MAPK activation, senescence, or SASP.
Conclusions:
- Simvastatin and rosuvastatin effectively downregulate OS-induced p38MAPK activation, senescence, and SASP in fetal membranes, with rosuvastatin showing a stronger effect.
- These statins may offer a therapeutic strategy to reduce PTB and pPROM by mitigating OS-driven senescence and inflammation.
- Progesterone is not effective in preventing OS-induced fetal membrane senescence and SASP.
Problem:
Oxidative stress (OS)-induced, p38 mitogen-activated protein kinase (p38MAPK)-mediated chorioamniotic senescence and inflammation (senescence-associated secretory phenotype [SASP]) are associated with parturition. In response to OS-inducing risk factors, premature senescence contributes to preterm premature rupture of the membranes (pPROM) and spontaneous preterm birth (PTB). We determined the effect of simvastatin, rosuvastatin, and progesterone in downregulating p38MAPK-mediated senescence and SASP.
Method Of Study:
Normal term, not-in-labor fetal membranes (n = 8) were exposed to cigarette smoke extract (CSE: OS inducer) alone or combined with simvastatin (100 and 200 ng/mL), rosuvastatin (100 and 200 ng/mL), and progesterone (10-6 mol/L). p38MAPK expression changes were studied by Western blot, senescence was determined by senescence-associated β-Galactosidase (SA-β-Gal) staining, and multiplex analysis determined changes associated with 4 SASP markers (IL-8, IL-10, TNF-α, and GM-CSF). A pairwise comparison between groups was conducted by ANOVA.
Results:
Compared to untreated controls, CSE induced p38MAPK-mediated senescence and SASP. CSE cotreatment with simvastatin and rosuvastatin significantly reduced p38MAPK activation, senescence (decrease in SA-β-Gal) and SASP markers, GM-CSF, and TNF, but not IL-8, while increasing anti-inflammatory IL-10 in a dose-dependent manner. Cotreatment of CSE and progesterone had no effect on reducing p38MAPK activation, senescence, or SASP.
Conclusion:
Both simvastatin and rosuvastatin downregulated OS-induced p38MAPK activation, senescence, and SASP, while rosuvastatin showed a pronounced effect. Progesterone did not reduce OS-induced fetal membrane senescence and SASP. Simvastatin or rosuvastatin may reduce the incidences of OS-associated PTB and pPROM by preventing premature senescence and SASP.
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