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

TY - JOUR

T1 - Repurposing simvastatin as a therapy for preterm labor

T2 - Evidence from preclinical models

AU - Boyle, Ashley K.

AU - Rinaldi, Sara F.

AU - Rossi, Adriano G.

AU - Saunders, Philippa T.K.

AU - Norman, Jane E.

N1 - Publisher Copyright: © 2019 The Author(s).

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - Contraction

KW - Inflammation

KW - Pregnancy

KW - Preterm birth

KW - Statins

UR - http://www.scopus.com/inward/record.url?scp=85061048333&partnerID=8YFLogxK

U2 - 10.1096/fj.201801104R

DO - 10.1096/fj.201801104R

M3 - Article

C2 - 30312114

AN - SCOPUS:85061048333

SN - 0892-6638

VL - 33

SP - 2743

EP - 2758

JO - Faseb Journal

JF - Faseb Journal

IS - 2

ER -