Repurposing simvastatin as a therapy for preterm labor: Evidence from preclinical models

Abstract

Preterm birth (PTB), the leading cause of neonatal morbidity and mortality, urgently requires novel therapeutic agents. Spontaneous PTB, resulting frompretermlabor, is commonly caused by intrauterine infection/ inflammation. Statins are well-established, cholesterol-lowering drugs that can reduce inflammation and inhibit vascular smooth muscle contraction. We show that simvastatin reduced the incidence of PTB in a validated intrauterine LPS-induced PTBmousemodel, decreased uterine proinflammatorymRNA concentrations (IL-6, Cxcl1, andCcl2), and reduced serumIL-6 concentration. Inhumanmyometrial cells, simvastatin reduced proinflammatory mediator mRNA and protein expression (IL-6 and IL-8) and increased anti-inflammatory cytokine mRNA expression (IL-10 and IL-13). Critically, simvastatin inhibited myometrial cell contraction, basally and during inflammation, and reduced phosphorylatedmyosin light chain concentration. Supplementationwithmevalonate and geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, abolished these anticontractile effects, indicating that theRho/Rho-associated protein kinase pathway is critically involved. Thus, simvastatin reduces PTB incidence in mice, inhibits myometrial contractions, and exhibits key anti-inflammatory effects, providing a rationale for investigation into the repurposing of statins to treat pretermlabor inwomen.