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Statins and preeclampsia

Abraham Tsur, Flora Kalish, Jordan Burgess, Nihar R Nayak, Hui Zhao, Kerriann M Casey, Maurice L Druzin, Ronald J Wong, David K Stevenson
INTRODUCTION: Statins induce heme oxygenase-1 (HO-1) expression in vitro and in vivo. Low HO-1 expression is associated with pregnancy complications, e.g. preeclampsia and recurrent miscarriages. Here, we investigated the effects of pravastatin on HO-1 expression, placental development, and fetal survival in mice with a partial HO-1 deficiency. METHODS: At E14.5, untreated pregnant wild-type (WT, n=13-18), untreated HO-1+/- (Het, n=6-9), and Het mice treated with pravastatin (Het+Pravastatin, n=12-14) were sacrificed...
January 2019: Placenta
Roxanne Hastie, Fiona C Brownfoot, Natasha Pritchard, Natalie J Hannan, Ping Cannon, Vi Nguyen, Kirsten Palmer, Sally Beard, Stephen Tong, Tu'uhevaha J Kaitu'u-Lino
Preeclampsia is a hypertensive disorder of pregnancy characterized by maternal endothelial dysfunction and end-organ damage. The antiangiogenic factor, sFlt-1 (soluble FMS-like tyrosine kinase-1) has been strongly implicated in the pathogenesis of preeclampsia. sFlt-1 is secreted into the maternal circulation where it antagonizes VEGF (vascular endothelial growth factor) and ultimately disrupts vascular homeostasis. However, the upstream mechanisms regulating release of sFlt-1 are poorly characterized. We investigated the roles of key prosurvival pathways, EGFR (epidermal growth factor receptor) signaling, and the mitochondria, in regulating sFlt-1 production...
January 14, 2019: Hypertension
Ridwan A Putra, Jusuf S Effendi, Wiryawan Permadi, Ria Bandiara, Prima N Fauziah
Preeclampsia is the major cause of both maternal and neonatal morbidity and mortality. Its insidence remains high and the management has not been established yet because its etiology and pathophysiological are still poorly understood. Theories regarding etiopathogenesis and management of preeclampsia have been postulated yet it remains controversial. Placental ischemic and angiogenic imbalance are suggested to be predisposing factors of preeclampsia. It is thereby targeted in prevention of preeclampsia. Unfortunately, both primary and secondary prevention using various supplements and drugs fails to exhibit good outcome...
July 30, 2018: Cellular and Molecular Biology
Mu-Yi Yang, Zhen-Yu Diao, Zhi-Yin Wang, Gui-Jun Yan, Guang-Feng Zhao, Ming-Ming Zheng, An-Yi Dai, Yi-Min Dai, Ya-Li Hu
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-κB pathway...
July 23, 2018: Journal of Biomedical Research
Ross A Carson, Anthony C Rudine, Serena J Tally, Alexis L Franks, Krystle A Frahm, Jacob K Waldman, Neerupma Silswal, Suban Burale, James V Phan, Uma R Chandran, A Paula Monaghan, Donald B DeFranco
Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthesis pathway (CBP), and are used for the prevention of cardiovascular disease. The anti-inflammatory effects of statins may also provide therapeutic benefits and have led to their use in clinical trials for preeclampsia, a pregnancy-associated inflammatory condition, despite their current classification as category X (i.e. contraindicated during pregnancy). In the developing neocortex, products of the CBP play essential roles in proliferation and differentiation of neural stem-progenitor cells (NSPCs)...
2018: PloS One
Serban M Maierean, Dimitri P Mikhailidis, Peter P Toth, Mariusz Grzesiak, Moshen Mazidi, Marek Maciejewski, Maciej Banach
Statins have several pleiotropic effects that have the potential to be beneficial during pregnancy. This study evaluates the available evidence for the teratogenicity of statins, and their utility in treating preeclampsia and dyslipidemia in pregnancy, as good alternatives in these domains are currently lacking. Areas covered: The possible teratogenicity of statins is a primary focus of this paper. We also evaluated for some possible non-teratogenic effects, such as changes in birth weight and rates of spontaneous abortion, among mothers exposed to statins during pregnancy...
May 2018: Expert Opinion on Investigational Drugs
Marie L Weber
Statins seem to positively influence the inflammatory, anti-angiogenic milieu of pregnancies with underlying placental ischemia by their pleiotropic effects. This might prevent, ameliorate and delay preeclampsia. To confirm the benefits of pravastatin on gestational age at birth as well as clinic and angiogenic markers in pregnancies at high-risk for preeclampsia, the Department of Obstetrics at the University Hospital Leipzig plans a randomized, double-blinded, placebo-controlled feasibility study.
February 2018: Zeitschrift Für Geburtshilfe und Neonatologie
Enrique Esteve-Valverde, Raquel Ferrer-Oliveras, Natàlia Gil-Aliberas, Antònia Baraldès-Farré, Elisa Llurba, Jaume Alijotas-Reig
Importance: We have performed a systematic search to summarize the role of statins for preventing and treating severe preeclampsia. Objective: The aim of this study was to examine whether pravastatin is a useful and safe alternative for treating preeclampsia during pregnancy. Evidence Acquisition: A systematic MEDLINE (PubMed) search was performed (1979 to June 2017), which was restricted to articles published in English, using the relevant key words of "statins," "pregnancy," "preeclampsia," "obstetrical antiphospholipid syndrome," and "teratogenicity...
January 2018: Obstetrical & Gynecological Survey
Burak Zeybek, Maged Costantine, Gokhan S Kilic, Mostafa A Borahay
INTRODUCTION: Statins are a class of drugs, which act by inhibiting the rate-limiting enzyme of cholesterol biosynthesis (3-hydroxy-3-methyl-glutaryl-CoA reductase). The inhibition of mevalonate synthesis leads to subsequent inhibition of downstream products of this pathway, which explains the pleiotropic effects of these agents in addition to their well-known lipid-lowering effects. Accumulating evidence suggests that statins might be beneficial in various obstetric and gynecologic conditions...
June 2018: Reproductive Sciences
Katie M Groom, Anna L David
Fetal growth restriction and related placental pathologies such as preeclampsia, stillbirth, and placental abruption are believed to arise in early pregnancy when inadequate remodeling of the maternal spiral arteries leads to persistent high-resistance and low-flow uteroplacental circulation. The consequent placental ischaemia, reperfusion injury, and oxidative stress are associated with an imbalance in angiogenic/antiangiogenic factors. Many interventions have centered on the prevention and/or treatment of preeclampsia with results pertaining to fetal growth restriction and small-for-gestational-age pregnancy often included as secondary outcomes because of the common pathophysiology...
February 2018: American Journal of Obstetrics and Gynecology
Vasiliki Katsi, Georgios Georgountzos, Manolis S Kallistratos, Ioannis Zerdes, Thomas Makris, Athanasios J Manolis, Petros Nihoyannopoulos, Dimitris Tousoulis
Preeclampsia has been linked to high morbidity and mortality during pregnancy. However, no efficient pharmacological options for the prevention of this condition are currently available. Preeclampsia is thought to share several pathophysiologic mechanisms with cardiovascular disease, which has led to investigations for the potential role of statins (HMG CoA reductase inhibitors) in its prevention and early management. Pravastatin seems to have a safer pharmacokinetic profile compared to other statins, however, the existing preclinical evidence for its effectiveness in preeclampsia treatment has been mostly restricted to animal models...
2017: Frontiers in Pharmacology
Caroline C Marrs, Maged M Costantine
Preeclampsia is a multisystem disorder that affects 3% to 5% of pregnant women and remains a significant source of short-term and long-term maternal and neonatal mortality and morbidity. Many professional societies recommend the use of low-dose aspirin to prevent preeclampsia in high-risk women. Owing to the similarities in pathophysiology between preeclampsia and atherosclerotic cardiovascular disease, and the encouraging data from preclinical and pilot clinical studies, pravastatin has been proposed for preventing preeclampsia...
March 2017: Clinical Obstetrics and Gynecology
Akihide Ohkuchi, Chikako Hirashima, Kayo Takahashi, Hirotada Suzuki, Shigeki Matsubara
The most common classifications of hypertensive disorders of pregnancy consist of chronic hypertension, gestational hypertension, preeclampsia (PE) and superimposed PE. A common final pathophysiology of PE is endothelial dysfunction. The most successful translational research model for explaining the cause-effect relationship in the genesis of PE is the angiogenic/angiostatic balance theory, involving soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF) and soluble endoglin (sEng). In a systematic review of articles on the prediction of early-onset PE using angiogenesis-related factors, we revealed that the prediction of early-onset PE in the first trimester is clinically possible, but the prediction of early-onset PE in the early third trimester might be ideal...
January 2017: Hypertension Research: Official Journal of the Japanese Society of Hypertension
Eleftheria Lefkou, Apostolos Mamopoulos, Themistoklis Dagklis, Christos Vosnakis, David Rousso, Guillermina Girardi
BACKGROUND: Administration of conventional antithrombotic treatment (low-dose aspirin plus low-molecular weight heparin [LDA+LMWH]) for obstetric antiphospholipid syndrome (APS) does not prevent life-threatening placenta insufficiency-associated complications such as preeclampsia (PE) and intrauterine growth restriction (IUGR) in 20% of patients. Statins have been linked to improved pregnancy outcomes in mouse models of PE and APS, possibly due to their protective effects on endothelium...
August 1, 2016: Journal of Clinical Investigation
Maged M Costantine
Pregnant women with antiphospholipid syndrome (APS) are at a high risk of obstetrical complications. The current standard of care, including the use of low-dose aspirin and heparin, has not been shown to prevent preeclampsia or intrauterine growth restriction (IUGR). Due to the similarities in pathophysiology among preeclampsia, IUGR, and atherosclerotic cardiovascular disease, statins have been proposed for treating and/or preventing these obstetrical complications. In this issue of the JCI, Lefkou et al. report on a small, observational trial that showed a dramatic improvement in both maternal and fetal/neonatal outcomes in women with APS given pravastatin after the onset of preeclampsia and/or IUGR compared with women in the control group...
August 1, 2016: Journal of Clinical Investigation
Fiona C Brownfoot, Stephen Tong, Natalie J Hannan, Roxanne Hastie, Ping Cannon, Tu'uhevaha J Kaitu'u-Lino
BACKGROUND: Preeclampsia is associated with the placental release of soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG). These anti-angiogenic factors cause hypertension and multi-organ injury. Pravastatin decreases placental secretion of sFlt-1 in vitro and is currently being examined in clinical trials as a potential treatment for preeclampsia. However, it is possible that different classes of statins may be more potent at decreasing sFlt-1 secretion. We compared the relative potency of three different generations of statins on sFlt-1 and sENG secretion from human endothelial cells, trophoblast cells, and placenta explants...
May 20, 2016: BMC Pregnancy and Childbirth
Antonio F Saad, Zaid M Diken, Talar B Kechichian, Shannon M Clark, Gayle L Olson, George R Saade, Maged M Costantine
OBJECTIVE: Using an animal model of preeclampsia induced by overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1), we previously showed that pravastatin prevents the development of a preeclampsia phenotype. Our objective is to determine whether pravastatin treatment may be explained by its effects on apoptotic/survival pathways in the placenta. METHODS: Pregnant CD1 mice at day 8 of gestation (length of gestation 19 days) were randomly allocated to injection via tail vein with either adenovirus carrying sFlt-1 or adenovirus carrying the murine immunoglobulin G2α Fc fragment (mFc virus control group)...
November 2016: Reproductive Sciences
Leonardo Ermini, Martin Post, Isabella Caniggia
The mevalonate pathway synthesizes intermediates and products such as cholesterol and nonsterol isoprenoids that are crucial for cell survival and function. In the human placenta, the prenylation of proteins, rather than cholesterol synthesis, represents the main "metabolic target" of mevalonate metabolism. Major cellular functions depend on isoprenylation including proliferation, migration, metabolism and protein glycosylation that are all crucial for proper development of the embryo and the placenta...
2017: Current Molecular Pharmacology
Charlotte J Oyston, Joanna L Stanley, Philip N Baker
INTRODUCTION: Preeclampsia is a disorder of pregnancy, typically characterized by hypertension and proteinuria observed after the 20th week of gestation. Preeclampsia has dire consequences for both maternal and neonatal health: it is associated with 50,000 - 100,000 annual deaths globally, as well as serious fetal and neonatal morbidity and mortality, including increased risk of fetal growth restriction and still birth. Despite the severe health, social, and economic costs of preeclampsia, currently the only curative therapy is delivery of the baby and placenta, which itself carries the associated risks of premature birth...
2015: Expert Opinion on Therapeutic Targets
Asif Ahmed
UNLABELLED: The exact aetiology of preeclampsia is unknown, but there is a good association with an imbalance in angiogenic growth factors and abnormal placentation (Ahmad and Ahmed, 2004). The incidence of preeclampsia is reduced by a third in smokers, but not in snuff users. Soluble Flt-1 (sFlt-1) and soluble endoglin (sEng) are increased prior to the clinical onset of preeclampsia. Animals exposed to high circulating levels of sFlt-1 and sEng elicit severe preeclampsia-like symptoms...
July 2014: Pregnancy Hypertension
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