Pravastatin alleviates lipopolysaccharide-induced placental TLR4 over-activation and promotes uterine arteriole remodeling without impairing rat fetal development

Abstract

Preeclampsia is associated with over-activation of the innate immune system in the placenta, in which toll-like receptor 4 (TLR4) plays an essential part. With their potent anti-inflammatory effects, statins have been suggested as potential prevention or treatment of preeclampsia, although evidence remains inadequate. Herewith, we investigated whether pravastatin could ameliorate preeclampsia-like phenotypes in a previously established lipopolysaccharide (LPS)-induced rat preeclampsia model, through targeting the TLR4/NF-kB pathway. The results showed that pravastatin reduced the blood pressure [maximum decline on gestational day (GD) 12, (101.33±2.49) mmHg vs. (118.3±1.37) mmHg, P<0.05] and urine protein level [maximum decline on GD9, (3,726.23±1,572.86) mg vs. (1,991.03±609.37) mg, P<0.05], which were elevated following LPS administration. Pravastatin also significantly reduced the rate of fetal growth restriction in LPS-treated rats (34.10% vs. 8.99%, P<0.05). Further pathological analyses suggested a restoration of normal spiral artery remodeling in preeclampsia rats by pravastatin treatment. These effects of pravastatin were associated with decreased TLR4/NF-kB protein levels in the placenta and IL-6/MCP-1 levels in serum. Additionally, no obvious abnormalities in fetal liver, brain, and kidney were found after administration of pravastatin. These results provide supportive evidence for use of pravastatin in preventing preeclampsia.

Keywords

preeclampsia / arteriole remodeling pravastatin / toll-like receptor 4 / fetal development

References

[1] Cotechini T, Komisarenko M, Sperou A, Inflammation in rat pregnancy inhibits spiral artery remodeling leading to fetal growth restriction and features of preeclampsia[J]. J Exp Med, 2014, 211(1): 165–179

[2] American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ task force on hypertension in pregnancy[J]. Obstet Gynecol, 2013, 122(5): 1122–1131.

[3] Redman CWG, Sacks GP, Sargent IL. Preeclampsia: An excessive maternal inflammatory response to pregnancy[J]. Am J Obstet Gynecol, 1999, 180(2 I):499–506.

[4] Chen W, Qian L, Wu F, Significance of toll-like receptor 4 signaling in peripheral blood monocytes of pre-eclamptic patients[J]. Hypertens Pregnancy, 2015, 34(4): 486–494.

[5] Xue P, Zheng M, Gong P, Single administration of ultra-low-dose lipopolysaccharide in rat early pregnancy induces TLR4 activation in the placenta contributing to preeclampsia[J]. PLoS One, 2015, 10(4): e0124001.

[6] Yang XL, Zhang JD, Duan L, Microglia activation mediated by toll-like receptor-4 impairs brain white matter tracts in rats[J]. J Biomed Res, 2017, 32: 136–144.

[7] Park YH, Seo SY, Lee E, Simvastatin induces apoptosis in castrate resistant prostate cancer cells by deregulating nuclear factor-kB pathway[J]. J Urol, 2013, 189(4): 1547–1552.

[8] Kong F, Ye B, Lin L, Atorvastatin suppresses NLRP3 inflammasome activation via TLR4/MyD88/NF-kB signaling in PMA-stimulated THP-1 monocytes[J]. Biomed Pharmacother, 2016, 82: 167–172.

[9] Zhu Z, Fang Z. Statin protects endothelial cell against ischemia reperfusion injury through HMGB1/TLR4 pathway[J]. Int J Cardiol, 2016, 203: 74

[10] Basraon SK, Costantine MM, Saade G, The effect of simvastatin on infection-induced inflammatory response of human fetal membranes[J]. Am J Reprod Immunol, 2015, 74(1): 54–61

[11] Esteve-Valverde E, Ferrer-Oliveras R, Gil-Aliberas N, Pravastatin for preventing and treating preeclampsia: a systematic review[J]. Obstet Gynecol Surv, 2018, 73(1): 40–55

[12] Girardi G. Pravastatin to treat and prevent preeclampsia. Preclinical and clinical studies[J]. J Reprod Immunol, 2017, 124: 15–20.

[13] Balan A, Szaingurtensolodkin I, Swissa SS, The effects of pravastatin on the normal human placenta: Lessons from ex-vivo models[J]. PLoS One, 2017, 12(2): e0172174

[14] Marrs CC, Costantine MM. Should we add pravastatin to aspirin for preeclampsia prevention in high-risk women?[J]. Clin Obstet Gynecol, 2017, 60(1): 161–168.

[15] Zhang Y, Hua Z, Zhang K, Therapeutic effects of anticoagulant agents on preeclampsia in a murine model induced by phosphatidylserine/phosphatidylcholine microvesicles[J]. Placenta, 2009, 30(12): 1065–1070.

[16] Zhou J, Xiao D, Hu Y, Gestational hypoxia induces preeclampsia-like symptoms via heightened endothelin-1 signaling in pregnant rats[J]. Hypertension, 2013, 62(3): 599–607

[17] Shen L, Diao Z, Sun H, Up-regulation of CD81 inhibits cytotrophoblast invasion and mediates maternal endothelial cell dysfunction in preeclampsia[J]. Proc Natl Acad Sci USA, 2017, 114(8): 1940–1945

[18] Gangooly S, Muttukrishna S, Jauniaux E. In-vitro study of the effect of anti-hypertensive drugs on placental hormones and angiogenic proteins synthesis in pre-eclampsia[J]. PLoS One, 2014, 9(9): e107644

[19] Litang Z, Hong W, Weimin Z, Serum NF-kBp65, TLR4 as biomarker for diagnosis of preeclampsia[J]. Open Med, 2017, 12(1): 399–402.

[20] Al-ofi EA, Anumba DO. Ligands of toll-like receptors 2/4 differentially alter markers of inflammation, adhesion and angiogenesis by monocytes from women with pre-eclampsia in co-culture with endothelial cells[J]. J Reprod Immunol, 2017, 121: 26–33.

[21] Deng F, Han F, Wu C. Expression and immune effect of toll-like receptor 4 in human trophoblast cells[J]. J Huazhong Univ Sci Technolog Med Sci, 2009, 29(3): 359–362.

[22] Soares MJ, Chakraborty D, Karim Rumi MA, Rat placentation: An experimental model for investigating the hemochorial maternal-fetal interface[J]. Placenta, 2012, 33(4): 233–243.

[23] Dong X, Shi D. Simvastatin alleviates pathology in a rat model of preeclampsia involving ERK/MAPK pathway[J]. Reprod Sci, 2017, 24(7): 1053–1061

[24] Cooper MK, Wassif CA, Krakowiak PA, A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis[J]. Nat Genet, 2003, 33(4): 508–513

[25] Caniggia I, Post M, Ermini L. Statins, mevalonate pathway and its intermediate products in placental development and preeclampsia[J]. Curr Mol Pharmacol, 2017, 10(2): 152–160

[26] Saad AF, Kechichian T, Yin H, Effects of pravastatin on angiogenic and placental hypoxic imbalance in a mouse model of preeclampsia[J]. Reprod Sci, 2014, 21(1): 138–145

[27] Fox KA, Longo M, Tamayo E, Effects of pravastatin on mediators of vascular function in a mouse model of soluble Fms-like tyrosine kinase-1-induced preeclampsia[J]. Am J Obstet Gynecol, 2011, 205(4): 366.e1–366.e5

[28] Singh J, Ahmed A, Girardi G. Role of complement component C1q in the onset of preeclampsia in mice[J]. Hypertension, 2011, 58(4): 716–724.

[29] Bauer AJ, Banek CT, Needham K, Pravastatin attenuates hypertension, oxidative stress, and angiogenic imbalance in rat model of placental ischemia-induced hypertension[J]. Hypertension, 2013, 61(5): 1103–1110.

[30] Pedroni SMA, Gonzalez JM, Wade J, Complement inhibition and statins prevent fetal brain cortical abnormalities in a mouse model of preterm birth[J]. Biochim Biophys Acta, 2014, 1842(1): 107–115

[31] Tijsseling D, Wijnberger LDE, Derks JB, Effects of antenatal glucocorticoid therapy on hippocampal histology of preterm infants[J]. PLoS One, 2012, 7(3): e33369

[32] O’Keefe J. A review of the hippocampal place cells[J]. Prog Neurobiol, 1979, 13(4): 419–439

[33] Schonewille M, Freark de Boer J, Mele L, Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice[J]. J Lipid Res, 2016, 57(8): 1455–1464

Acknowledgments

This work was funded by the following Grants: National Natural Science Foundation of China, Grant/Award Number: 81370724, 81571463 and 81401225; Innovative Research Program for Postgraduate in Higher Education Institutions of Jiangsu Province for the year 2016, Grant/Award Number: KYLX16_1111.

We thank Professor Juan Li for assistance with the experiments, Professor Biyun Xu for suggestions on statistical analysis and Professor Yan Zhou for valuable discussion.

RIGHTS & PERMISSIONS

2018 2018 by the Journal of Biomedical Research.