Gestational NSAIDs distinctly reprogram cardiac injury in preeclamptic rats: Roles of cyclooxygenase, apoptotic and autophagic trails.

Aims: Considering the role of cyclooxygenases (COX) in placental programming induced by preeclampsia (PE), we investigated whether gestational exposure to nonsteroidal antiinflammatory drugs (NSAIDs) with different COX-1/2 selectivity would variably modulate pre- and postnatal (weaning time, i.e. 3 weeks after delivery) cardiovascular manifestations of PE.
Materials and Methods: PE was induced by oral administration of N ^ω -nitro-L-arginine methyl ester (L-NAME, 50 mg/kg/day for 7 days) to pregnant rats starting from day 14 of gestation. Rats were treated simultaneously with celecoxib (10 mg/kg/day), diclofenac (0.5 mg/kg/day), or naproxen (1 mg/kg/day).
Key Findings: Tail-cuff measurements revealed a higher systolic blood pressure (SBP) in PE mothers at gestational day 20 (GD20). More exaggerated rises in prenatal SBP were noted in PE rats treated with celecoxib but not diclofenac or naproxen. Higher levels of serum creatine and kinase MB (CK-MB), a biomarker of cardiac damage, were demonstrated in weaning PE rats and this effect was suppressed by naproxen only. Additionally, naproxen was the most effective among all 3 NSAIDs in diminishing the PE-induced surges in (i) cardiomyocyte cross-sectional area, (ii) cardiac COX-1/COX-2 activities, (iii) arachidonate metabolites (PGE ₂ , PGF2α, and TXA2), (iv) caspase-3 and beclin-1 expressions. By contrast, the PE-related increments in cardiac expression of antiangiogenic (sFlt-1, and endoglin-1) and inflammatory (nuclear factor kappa B, NF-κB) factors were indiscriminately reduced by all NSAIDs.
Significance: Compared with celecoxib or diclofenac, naproxen appears to be the most advantageous in minimizing cardiac damage in weaning PE rats due to its synchronized downregulatory effects on cyclooxygenase, apoptotic, and autophagic pathways.
Competing Interests: Declaration of competing interest None.
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