Phosphoproteomics reveals the apoptotic regulation of aspirin in the placenta of preeclampsia-like mice.

Preeclampsia (PE) is a severe gestational complication, and dysfunctional placenta plays an essential role in PE pathogenesis. Although low-dose aspirin is currently the most promising prophylactic drug for PE prevention, the exact mechanism of aspirin remains unclear. A previous study reported that treatment with low-dose aspirin could ameliorate PE-like symptoms in lipopolysaccharide (LPS)-induced PE-like mouse model. This study aimed to uncover the potential mechanism of aspirin action in PE through quantitative phosphoproteomics comparison. We established the following four groups: a control (CTRL) group, an LPS-treated (L) group, an LPS + aspirin co-treatment (LA) group, and an aspirin-treated (A) group. A total of 4350 phosphosites and 4170 phosphopeptides from 1866 phosphoproteins were identified in the placenta on embryonic day 13.5. Among the significantly altered phosphoproteins identified, apoptosis-related pathways were significantly regulated in both the L group vs. CTRL group and the LA group vs. L group comparisons. We demonstrated that apoptosis was increased in the placenta of PE-like mice and was inhibited in the LA group by quantify the apoptosis-positive cells and the protein levels of cleaved caspase 3, 8, and 9. Moreover, the phosphorylation of HSP90β (S254) and GSK3β (Y216) may be a crucial factor in the aspirin-mediated regulation of apoptosis according to protein-protein interaction analysis. This study revealed that apoptosis regulation is a mechanism of aspirin action in PE, particularly in women with over-activated inflammation. The phosphorylation of HSP90β (S254) and GSK3β (Y216) could be the key intervention targets.
Competing Interests: None.
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