Pravastatin as the statin of choice for reducing pre-eclampsia-associated endothelial dysfunction

Alwis, Natasha de; Beard, Sally; Mangwiro, Yeukai; Binder, Natalie; Kaitu’u-Lino, Tu’uhevaha J; Brownfoot, Fiona; Tong, Stephen; Hannan, Natalie J.

doi:10.1016/j.preghy.2020.03.004

Cited by 35 publications

(28 citation statements)

References 35 publications

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“…In a similar study, proton pump inhibitors were shown to be able to ameliorate TNF-α-induced endothelial dysfunction of HUVECs and uterine microvascular cells, by blocking VCAM-1 expression, leukocytes adhesion to endothelium and irregular tube formation [69]. Other pregnancy-safe medicines including pravastatin were also investigated for the same purpose and showed promising results in restoring endothelial functional dysfunctions [66,70,71].…”

Section: In Vitro Models Of Endothelial Dysfunction In Preeclampsiamentioning

confidence: 97%

“…Endothelin 1 (ET-1) and vascular cell adhesion molecule 1 (VCAM-1) are markers of endothelial dysfunction that are also elevated in preeclampsia. ET-1 is a powerful vasoconstrictor released from endothelial cells and VCAM-1 is a cell surface adhesion molecule involved in leukocyte-endothelial cells signal transduction [66]. Both of these molecules when elevated in preeclampsia can lead to hypertension and a reduction in blood flow to the major organs.…”

Section: In Vitro Models Of Endothelial Dysfunction In Preeclampsiamentioning

confidence: 99%

“…If left untreated, end organ damage likely follows. Research investigating therapeutic options for endothelial dysfunction utilises either HUVECs or uterine microvascular endothelial cells treated with combination therapy to help restore angiogenic balance and hence ameliorate endothelial dysfunction in preeclampsia [64,66]. Brownfoot et al [67] previously identified metformin and sulfasalazine to each individually reduce secretion levels of endothelial sFlt-1 and sEng [68].…”

Section: In Vitro Models Of Endothelial Dysfunction In Preeclampsiamentioning

confidence: 99%

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Considerations to Model Heart Disease in Women with Preeclampsia and Cardiovascular Disease

Ming¹,

Sesperez²,

Ben-Sefer³

et al. 2021

Preprint

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Preeclampsia is a multifactorial cardiovascular disorder diagnosed after 20 weeks of gestation that is the leading cause of death for both mothers and babies in pregnancy. The pathophysiology remains poorly understood due to variability and unpredictability of disease manifestation when studied in animal models. After preeclampsia, both mothers and offspring have a higher risk of cardiovascular disease (CVD) including myocardial infarction or heart attack and heart failure (HF). Myocardial infarction is an acute myocardial damage that can be treated through reperfusion, however, that therapeutic approach leads to ischemic/reperfusion injury (IRI) often leading to HF. In this review, we compared the current in vivo, in vitro and ex vivo model systems used to study preeclampsia, IRI and HF. Future studies aiming at evaluating CVD in preeclampsia patients could benefit from novel models that better mimic the complex scenario described in this article.

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Section: In Vitro Models Of Endothelial Dysfunction In Preeclampsiamentioning

confidence: 97%

Section: In Vitro Models Of Endothelial Dysfunction In Preeclampsiamentioning

confidence: 99%

Section: In Vitro Models Of Endothelial Dysfunction In Preeclampsiamentioning

confidence: 99%

See 1 more Smart Citation

Considerations to Model Heart Disease in Women with Preeclampsia and Cardiovascular Disease

Ming¹,

Sesperez²,

Ben-Sefer³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…36 There is also experimental in vitro evidence that it resolves endothelial dysfunction in several experimental assays (reduces expression of vascular cell adhesion molecule 1 [VCAM-1] and ET-1 and leukocyte adhesion on endothelial cells and increases endothelial cell migration and adhesion). 36,37 This means that it could beneficially act on both the placental and maternal vascular diseases (Figure 1).…”

Section: Search Strategymentioning

confidence: 99%

Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia

Tong

Kaitu’u-Lino

Hastie

et al. 2022

American Journal of Obstetrics and Gynecology

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There has been increasing research momentum to identify new therapeutic agents for the prevention or treatment of preeclampsia, drugs that can affect the underlying disease pathophysiology. Molecular targets of candidate treatments include oxidative stress, antiangiogenic factors, and the angiotensin, nitric oxide, and proinflammatory pathways. The proposed treatments undergoing preclinical and clinical trial evaluation are thought to act on placental or endothelial disease or both. Most have adopted the pragmatic strategy of repurposing drugs. Of all the therapeutic agents proposed, pravastatin has received the most interest. There are preclinical studies showing that it has pleiotropic actions that favorably impact on multiple molecular targets and can resolve a preeclampsia phenotype in many animal models. An early phase clinical trial suggests that it may have therapeutic activity. Several large prevention trials are planned or ongoing and, when completed, could definitively address whether pravastatin can prevent preeclampsia. Proton-pump inhibitors, metformin, and sulfasalazine are other drugs with preclinical evidence of multiple molecular actions that could resolve the pathophysiology of preeclampsia. These agents are also currently being evaluated in clinical trials. There have been many recent preclinical studies identifying the potential of numerous natural compounds to treat preeclampsia, such as plant extracts and micronutrients that have potent anti-inflammatory or antioxidant activity. Recent preclinical studies have also proposed novel molecular-targeted strategies, such as monoclonal antibodies targeting tumor necrosis factor alpha, placental growth factor, and short interfering RNA technology, to silence the gene expression of soluble fmslike tyrosine kinase-1 or angiotensinogen. Other treatment approaches that have transitioned to human trials (ranging from single-arm to phase III trials that have been completed or are ongoing) include folic acid, nitric oxide donors (such as L-arginine), recombinant antithrombin III, digoxin immune antigen-binding fragment, and melatonin. There have been case series showing the removal of circulating soluble fms-like tyrosine kinase-1 may help stabilize the disease and prolong pregnancy. Interestingly, there are case reports suggesting that monoclonal antibody eculizumab (complement inhibitor) may have therapeutic potential. If new agents are discovered that are proven to be effective in preventing or treating preeclampsia, the potential to improve global maternal and perinatal health will be significant.

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“…In fact, a similar thiazide, hydroflumethiazide, is currently used for preeclampsia management [47]. On the other hand, even when the effect of simvastatin during preeclampsia in unknown, a close statin (pravastatin) is known to reduce the endothelial dysfunction associated with preeclampsia [48]. Moreover, oubain and digitoxin are capable of inhibiting sFlt-1 production [49], which is elevated in preeclampsia and is directly associated with possible preeclampsia pathogenesis mechanisms.…”

Section: Drug Repurposingmentioning

confidence: 99%

A Multi-Objective Approach for Drug Repurposing in Preeclampsia

et al. 2021

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Preeclampsia is a hypertensive disorder that occurs during pregnancy. It is a complex disease with unknown pathogenesis and the leading cause of fetal and maternal mortality during pregnancy. Using all drugs currently under clinical trial for preeclampsia, we extracted all their possible targets from the DrugBank and ChEMBL databases and labeled them as “targets”. The proteins labeled as “off-targets” were extracted in the same way but while taking all antihypertensive drugs which are inhibitors of ACE and/or angiotensin receptor antagonist as query molecules. Classification models were obtained for each of the 55 total proteins (45 targets and 10 off-targets) using the TPOT pipeline optimization tool. The average accuracy of the models in predicting the external dataset for targets and off-targets was 0.830 and 0.850, respectively. The combinations of models maximizing their virtual screening performance were explored by combining the desirability function and genetic algorithms. The virtual screening performance metrics for the best model were: the Boltzmann-Enhanced Discrimination of ROC (BEDROC)α=160.9 = 0.258, the Enrichment Factor (EF)1% = 31.55 and the Area Under the Accumulation Curve (AUAC) = 0.831. The most relevant targets for preeclampsia were: AR, VDR, SLC6A2, NOS3 and CHRM4, while ABCG2, ERBB2, CES1 and REN led to the most relevant off-targets. A virtual screening of the DrugBank database identified estradiol, estriol, vitamins E and D, lynestrenol, mifrepristone, simvastatin, ambroxol, and some antibiotics and antiparasitics as drugs with potential application in the treatment of preeclampsia.

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Pravastatin as the statin of choice for reducing pre-eclampsia-associated endothelial dysfunction

Cited by 35 publications

References 35 publications

Considerations to Model Heart Disease in Women with Preeclampsia and Cardiovascular Disease

Considerations to Model Heart Disease in Women with Preeclampsia and Cardiovascular Disease

Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia

A Multi-Objective Approach for Drug Repurposing in Preeclampsia

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