The effects of pravastatin on the normal human placenta: Lessons from ex-vivo models

Balan, Adelina; Szaingurten-Solodkin, Irit; Swissa, Shani S.; Feinshtein, Valeria; Huleihel, Mahmoud; Holcberg, Gershon; Dukler, Doron; Beharier, Ofer

doi:10.1371/journal.pone.0172174

Cited by 25 publications

(17 citation statements)

References 45 publications

(67 reference statements)

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“…It has been shown that eNOS augments fetoplacental blood flow, placental vascularization, and fetal growth in mice (20). In addition, it has been reported that PRAV protects the endothelium by activating eNOS independent of its cholesterol-lowering actions (21). Moreover, an increase in the synthesis and activity of eNOS was found in human placental cotyledons perfused with PRAV (22).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Pravastatin and-L-arginine combination improves umbilical artery blood flow and neonatal outcomes in dichorionic twin pregnancies through an nitric oxide-dependent vasorelaxant effect

Jurisic

Jurisic²,

Lefkou³

et al. 2018

Vascular Pharmacology

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The increase in fetal and neonatal morbidity and mortality associated with twin pregnancies correlates with an increased risk of preterm delivery, low birth weight, and intrauterine growth restriction (IUGR). Although the pathogenesis of IUGR is unclear and thus management remains a major challenge, feto-placental blood vessels are compromised, and altered umbilical blood flow is observed. In this pilot observational study we investigated the effects of pravastatin plus l-arginine on umbilical artery (umb art) blood flow. Between 2013 and 2016, five women received daily doses l-arginine and pravastatin when an umb art pulsatility index above limits for gestational age was observed and concerns about selective growth restrictions arose. All patients showed selective absent or reversed end-diastolic umbilical artery Doppler flow (AREDV) associated with increased perinatal mortality. Pravastatin (PRAV) plus l-arginine (l-Arg) treatment diminished umb art resistance significantly and allowed pregnancy to continue. No signs of acidosis or hypoxia, normal cardiotocography tracing, normal fetal movement and fetal weight gain were observed in the twins that showed abnormal umb art Dopplers. All neonates were born around 33 weeks (median 33 weeks, IQR [31.4-33.0]), thus diminishing substantially the chances for any prematurity-associated adverse neonatal outcomes. The infants now show normal growth and development. In in vitro studies, pravastatin induced relaxation of aortic rings. Murine studies identified were performed to investigate the mechanism behind PRAV+L-Arg beneficial effects. A nitric oxide (NO)-dependent synergistic vasorelaxant effect of PRAV+L-Arg was demonstrated using aortic rings. Increased levels of placental NO and increased synthesis of eNOS in placental endothelial cells were observed in mice treated with PRAV+L-Arg compared to untreated mice and mice treated with PRAV- or L-Arg alone. This study suggests that PRAV plus L-Arg might be a good therapeutic option to improve blood flow in umbilical arteries prolonging pregnancy and improving pregnancy outcomes in twins. A RCT should be organized to confirm these results.

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Section: Accepted Manuscriptmentioning

confidence: 99%

Pravastatin and-L-arginine combination improves umbilical artery blood flow and neonatal outcomes in dichorionic twin pregnancies through an nitric oxide-dependent vasorelaxant effect

Jurisic

Jurisic²,

Lefkou³

et al. 2018

Vascular Pharmacology

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“…However, it is worth noting that recent studies have demonstrated that pravastatin has a favorable pharmacokinetic profile in pregnancy. 29 Pravastatin therapy: A case report…”

Section: Clinical Researchmentioning

confidence: 99%

Pravastatin for preeclampsia: From animal to human

Kumasawa

Iriyama

Nagamatsu

et al. 2020

J of Obstet and Gynaecol

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Preeclampsia is characterized by the emergence of hypertension and proteinuria after 20 weeks of pregnancy, and it threatens both maternal and fetal lives if it proceeds unabated. Despite numerous studies, thus far the only fundamental therapy for preeclampsia is termination of pregnancy, leading to preterm birth. Furthermore, preeclamptic women are reported to be at risk for cardiovascular diseases for 10 years after delivery. Therefore, preventative and therapeutic strategies for preeclampsia are required. Recently, statins have been reported to improve the regeneration of vascular endothelium, and pravastatin has attracted attention as a potential preventative or therapeutic candidate for preeclampsia. Pravastatin has been demonstrated to have preventative effects in preeclampsia model mice, and a large volume of human data from pregnant women taking statins supports the safety of these drugs. Moreover, small clinical trials have reported that pravastatin has strong preventative or therapeutic effects on preeclampsia and it has the potential to improve the prognosis of pregnant women, fetuses and neonates affected by this condition.

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“…They are commonly applied in cardiovascular diseases. 6 Moreover, more and more reports showed that statins can effectively resist myocardial infarction and improve survival rate, inhibit inflammation and apoptosis of cells, stabilize artery plaque, maintain endothelial function and eliminate free radicals. 7 – 10 Pravastatin belongs to statins.…”

Section: Introductionmentioning

confidence: 99%

<p>Protective Effect of Pravastatin on Myocardial Ischemia Reperfusion Injury by Regulation of the miR-93/Nrf2/ARE Signal Pathway</p>

Liu¹,

Zhang²,

Zhao³

et al. 2020

DDDT

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Purpose: This research intended to study the mechanism of pravastatin in myocardial ischemia reperfusion (I/R) injury. Patients and Methods: Altogether 70 male rats were selected and grouped into Sham operation group (Sham group), ischemia reperfusion group (I/R group), pravastatin pretreatment group (I/R+P group), I/R+miR-93-mimics, I/R+P+miR-93-mimics, I/R+Nrf2 siRNA, and I/R+P+Nrf2 siRNA group. The myocardial function of each group was detected. Results: Myocardial I/R injury could lead to abnormal myocardial enzyme activity, inflammatory reaction and oxidative stress. However, pravastatin could significantly inhibit the activity of myocardial enzymes, alleviate inflammatory reaction and inhibit oxidative stress reaction, thus playing a protective role. Furthermore, cell experiments showed that pravastatin can alleviate the injury of H9C2 myocardial cells caused by I/R, inhibit the apoptosis of myocardial cells, and lead to a significant reduction in pro-apoptotic genes Bax, caspase-3 and caspase-9 transcription levels, an obvious increase in anti-apoptotic gene Bcl-2, and an increase in cell activity. After I/R induced injury, miR-93 level was significantly up-regulated and Nrf2 level was down-regulated. Over-expression of miR-93 or inhibition of Nrf2 expression would lead to further aggravation of I/R myocardial injury, increase the apoptosis rate of cells and decrease the activity of myocardial cells. Pravastatin administration could inhibit miR-93, activate and promote Nrf2 in myocardial tissue, and promote protein expression of downstream regulatory genes HO-1 and NQO1. In the I/R model, pravastatin was given. Over-expression of miR-93 or silencing Nrf2 could reverse the therapeutic effect of pravastatin on I/R. Conclusion: Pravastatin acts as a protector on myocardial ischemia reperfusion injury by regulating miR-93/Nrf2/ARE signaling pathway.

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The effects of pravastatin on the normal human placenta: Lessons from ex-vivo models

Cited by 25 publications

References 45 publications

Pravastatin and-L-arginine combination improves umbilical artery blood flow and neonatal outcomes in dichorionic twin pregnancies through an nitric oxide-dependent vasorelaxant effect

Pravastatin and-L-arginine combination improves umbilical artery blood flow and neonatal outcomes in dichorionic twin pregnancies through an nitric oxide-dependent vasorelaxant effect

Pravastatin for preeclampsia: From animal to human

<p>Protective Effect of Pravastatin on Myocardial Ischemia Reperfusion Injury by Regulation of the miR-93/Nrf2/ARE Signal Pathway</p>

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